A randomized, double-blind, placebo-controlled phase III study evaluating the preventive effect of diclofenac cream on capecitabine-related hand-foot syndrome: Study protocol of J-SUPPORT2401/JORTC-SUP06 (J-DIRECT)

A randomized, double-blind, placebo-controlled phase III study evaluating the preventive effect of diclofenac cream on capecitabine-related hand-foot syndrome: Study protocol of J-SUPPORT2401/JORTC-SUP06 (J-DIRECT) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A randomized, double-blind, placebo-controlled phase III study evaluating the preventive effect of diclofenac cream on capecitabine-related hand-foot syndrome: Study protocol of J-SUPPORT2401/JORTC-SUP06 (J-DIRECT) Yohei Iimura, Hiroshi Ishiguro, Hironobu Hashimoto, Masanori Nojima, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6299256/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 14 May, 2025 Read the published version in International Journal of Clinical Oncology → Version 1 posted 5 You are reading this latest preprint version Abstract Background Clinical evidence on preventive therapy for capecitabine-induced hand-foot syndrome (HFS) is limited, and moisturizing and avoiding local pressure are recommended in guidelines. Although the precise pathogenesis and mechanisms of HFS remain unclear, inflammatory reactions are thought to be involved. The preventive effects of topical diclofenac gel have been reported from India. However, the trial did not evaluate its preventive effect for the sole, and the HFS incidence in the control group was lower than that in previous reports. Therefore, this study aims to confirm the preventive effects of diclofenac sodium 0.1% cream for capecitabine-induced HFS. Methods This is a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. Patients scheduled to receive capecitabine-containing chemotherapy are enrolled, and participants are prophylactically treated with topical diclofenac sodium 0.1% cream or placebo alongside standard preventive therapy. The primary endpoint is an incidence of grade 2 HFS within 3 months. The secondary endpoints include time to onset of HFS, incidences of dose reduction, schedule delay, discontinuation caused by capecitabine-induced HFS, dose intensity of capecitabine, an incidence of grade ≥ 2 peripheral sensory neuropathy, incidences of other capecitabine-related adverse events (nausea, vomiting, appetite loss, diarrhea, oral mucositis, pigmentation, abnormality of liver and renal functions, and neutropenia). Discussion If this study meets the primary endpoint, a new standard preventive therapy for HFS will be established. Moreover, the use of topical diclofenac cream alongside high-dose capecitabine may enhance chemotherapy efficacy. Capecitabine-induced hand-foot syndrome topical diclofenac cream protocol Figures Figure 1 Introduction Hand-foot syndrome (HFS) is the most common adverse event induced by capecitabine, often deteriorating patient’s quality of life (QOL) [ 1 ]. In randomized controlled trials (RCTs) of systemic chemotherapy for colorectal cancer, the incidence of any grade HFS caused by capecitabine have been reported to be approximately 30–80% [ 2 – 10 ], whereas real-world data suggest it is over 90% [ 11 ]. Severe HFS causes symptoms such as swelling, blisters, desquamation, and ulcers, often leading to treatment interruptions, delays in the treatment schedule, dose reduction, and discontinuation of capecitabine. One study showed that 17–24% of patients with metastatic colorectal cancer receiving capecitabine monotherapy required dose and schedule modifications due to HFS [ 12 ]. Additionally, while it has been reported that dose intensity of capecitabine influences the outcomes of adjuvant chemotherapy for colon cancer [ 13 ], moderate or severe HFS requires treatment modifications (interruption and/or dose reduction) [ 14 ]. Therefore, managing HFS is crucial not only for maintaining patient’s QOL but also for ensuring the therapeutic efficacy of capecitabine [ 15 ]. However, a standard preventive therapy has not been established due to inconsistent results regarding the effectiveness of topical urea [ 16 , 17 ], exfoliating agents [ 18 ], celecoxib [ 19 , 20 ], vitamin E [ 21 ], and pyridoxine [ 22 ] for HFS. Currently, moisturizing and avoiding local pressure [ 23 – 25 ] are recommended as standard management methods for preventing capecitabine-induced HFS [ 26 ]. The mechanism of HFS involves the inhibition of the skin basal cell proliferation, drug secretion from the eccrine sweat glands, the involvement of drug degradation products [ 15 , 27 ], and an inflammatory response triggered by interleukin (IL)-1a, IL-1b, IL-6, and reactive oxygen species [ 28 ]. Based on this rationale, a large phase III study demonstrated that celecoxib has a preventive effect on HFS. However, its clinical use has been limited because of concerns about adverse events caused by the long-term use of non-steroidal anti-inflammatory drugs (NSAIDs). Moreover, clinical trials have evaluated the preventive effects of medium-class topical steroids [ 29 ] and topical diclofenac [ 30 ]. Corticosteroids exert their anti-inflammatory effects by inhibiting the release of chemical mediators. Oral dexamethasone (8 mg/day, followed by tapering) was administered to patients with pegylated liposomal doxorubicin-induced HFS in a prospective study [ 31 ], which reported that patients receiving dexamethasone required fewer treatment modifications, such as schedule delays or dose reductions than those not receiving dexamethasone. Other case reports have suggested that corticosteroids may be effective against cytarabine-and vinorelbine-induced HFS [ 32 , 33 ]. NSAIDs inhibit the production of cyclooxygenase (COX)-2, which is believed to contribute to the development of HFS [ 34 ]. Thus, anti-inflammatory agents may help prevent HFS caused by cytotoxic anti-tumor agents. Although the effectiveness of oral COX-2 inhibitors has been reported [ 19 , 20 ], safety concerns remain. Since topical formulations offer better safety by reducing the systemic effects of NSAIDs, the topical use of anti-inflammatory agents such as corticosteroids and NSAIDs is expected to prevent HFS without major safety concerns. Recently, the preventive efficacy of topical diclofenac was reported in India (D-TORCH study) [ 35 ], demonstrating that the prophylactic administration of topical diclofenac reduced the frequency of grade ≥ 2 HFS by 11.2% (3.8% vs 15.0%). However, the incidence of HFS in the placebo group of the D-TORCH study was substantially lower than that in other Asian studies (Table 1 ). Additionally, the D-TORCH study evaluated the effectiveness of topical diclofenac only on the hands, not the soles. Furthermore, while the study used a diclofenac gel base, the isopropanol in the gel may cause skin dryness and irritation, potentially worsening HFS symptoms. A cream based formulation is generally considered more suitable than a gel for preventing HFS. Table 1 Difference of the incidence of HFS induced by capecitabine in India (D-TORCH study) and other Asian countries in randomized controlled trials Incidence rate of HFS (any grade) Incidence rate of HFS (grade 2 or 3) Incidence rate of HFS (≥ grade 3) Number of patients % % % Country Intervention Blind Intervention Control Intervention Control Intervention Control Intervention Control China 2010 [ 19 ] Celecoxib No 51 50 29 52 11.76 30 1.96 10 China 2012 [ 20 ] Celecoxib No 68 71 57.4 74.6 14.7 29.6 2.9 8.5 South Korea 2010 [ 44 ] Pyridoxine Yes 180 180 64 76.1 12 15.4 3.3 5 Japan 2014 [ 45 ] Pyridoxine No 30 30 NA NA 60 60 NA NA Singapore 2017 [ 46 ] Pyridoxine Yes 105 105 61 66 32 37 4 2 Japan 2018 [ 47 ] Pyridoxine No 66 67 77 69 34 34 4 4 Japan 2020 [ 48 ] Eppikajutsuto (Kampo medicine) No 10 12 70 83.3 40 50 20 8.3 China 2021 [ 18 ] Lithium containing topical and moisturizing cream Yes 51 54 56.8 75.9 4.8 16.7 6.0 16.7 India 2020 [ 36 ] Structured teaching module Yes 135 134 64.4 62.5 33.3 32.8 5.2 6.8 India 2024 [ 35 ] Topical diclofenac Yes 130 133 6.1 18.1 3.8 15 2.3 5.3 This multicenter, randomized, double-blind, placebo-controlled, phase 3 trial aims to confirm the preventive effect of diclofenac sodium 0.1% cream for capecitabine-induced HFS. Methods Study design This is a multicenter, randomized, double-blind, placebo-controlled, phase 3 study. The study protocol was reviewed and approved by the certified Clinical Research Review Board of the University of Tokyo (approval number 2024505SP). The study is being conducted in compliance with the Clinical Trials Act in Japan and registered in the Japan Registry of Clinical Trials (jRCT) as jRCTs031240705. Participants The following patients are included in this study: (i) patients with colorectal, breast, or gastric cancer planned to receive chemotherapy containing capecitabine (≥ 800 mg/m 2 ); (ii) Eastern Cooperative Oncology Group performance status of 0–1, (iii) aged ≥ 18 years; and (iv) providing written informed consent. Exclusion criteria are as follows: (i) history of aspirin-induced asthma; (ii) presence of other skin diseases, skin lesions due to chemotherapy on the palms or soles, or dermatitis that makes it difficult to evaluate the efficacy of the study drug; (iii) history of hypersensitivity to local diclofenac; (iv) conditions requiring the constant use of steroids or NSAIDs; (v) scheduled to receive other anti-tumor agents (e.g. multi kinase inhibitors for anti-angiogenesis) that may interfere with the evaluation of efficacy of the study drug; (vii) pregnancy, breast feeding, or inablility to adhere to contraception during the study period; and (viii) sensory palsy in the palms or soles. Randomization After confirming eligibility, patients are registered using an independent central registration system. They are randomized in a 1:1 ratio to receive either diclofenac sodium 0.1% cream or a placebo cream using the minimization method, adjusted for sex (male vs. female), planned dose of capecitabine (≥ 800 mg/m 2 , < 1000 mg/m 2 , ≥ 1000, < 1250 mg/m 2 , ≥ 1250 mg/m 2 ), and participating institution. Chemotherapy Combination with other anti-tumor agents (e.g. oxaliplatin) and radiation (except for the palms and soles) is allowed if it includes capecitabine (≥ 800 mg/m 2 ). However, multi-kinase inhibitors (e.g., lapatinib) will not be allowed. Dose interruptions, delays, reductions, and discontinuations are allowed at each physician’s discretion. Intervention Both diclofenac sodium 0.1% cream and placebo are white cream products. The hydrophilic cream, which is the base material of diclofenac sodium 0.1% cream, is selected as the placebo. Since there is no noticeable difference in appearance or odor, double-blindness is ensured. Topical diclofenac sodium 0.1% cream or placebo is applied to the palms and soles twice daily in the morning and evening. More than one fingertip unit (one fingertip unit provides 0.5 g) of the study drug is applied to each palm and sole. This preventive treatment is initiated in the evening on day 1 and continued throughout the study period. All patients receive standard self-care education (e.g., maintaining cleanliness, avoiding strenuous exercise and pressure, and using sun protection) at the start of chemotherapy. Clinical pharmacists monitor the volume of study drugs used by checking the remaining amount and educate the patients to improve their adherence, if necessary. Prohibited therapy and drugs The following treatments or concomitant use of drugs are prohibited: (i) cancer treatment other than the capecitabine-based chemotherapy (localized radiation therapy excluding the palm or sole is allowed), (ii) continuous use of other topical corticosteroids or NSAIDs on the palms or soles, (iii) continuous use of NSAIDs, (iv) continuous use of pyridoxine, (v) use of multi-kinase inhibitors. Discontinuation of interventions Interventions are discontinued if any of the following events occurs: (i) discontinuation of capecitabine for any reason, (ii) withdrawal of consent, (iii) serious adverse events induced by the study drugs, and (iv) use of prohibited therapies or drugs. Optimal medical care without the study drugs is guaranteed to participants who discontinue or deviate from the intervention protocols. Evaluation Patients complete a self-report check sheet daily to document symptoms of HFS and adherence to the study drug. Patient’s symptoms and laboratory tests results are reviewed at every visit, and the severity of HFS is assessed by the clinical pharmacist and attending physician by referring to the self-reported adverse events (Tables 2 and 3 ). Evaluators will be undergo regular training to ensure data quality. Table 2 Assessment schedule Chemotherapy period (weeks) Pretreatment 3 6 9 12 Performance status ✓ ✓ ✓ ✓ ✓ Blood test ✓ ✓ ✓ ✓ ✓ Hand-foot syndrome ✓ ✓ ✓ ✓ Peripheral sensory neuropathy ✓ ✓ ✓ ✓ Nausea ✓ ✓ ✓ ✓ Vomiting ✓ ✓ ✓ ✓ Appetite loss ✓ ✓ ✓ ✓ Diarrhea ✓ ✓ ✓ ✓ Oral mucositis ✓ ✓ ✓ ✓ Pigmentation ✓ ✓ ✓ ✓ Abnormality of liver function ✓ ✓ ✓ ✓ Abnormality of renal function ✓ ✓ ✓ ✓ Neutropenia ✓ ✓ ✓ ✓ Self-report (adverse events) ✓ ✓ ✓ ✓ Self-report (self-adherence) ✓ ✓ ✓ ✓ Dose of chemotherapy ✓ ✓ ✓ ✓ Postponement of chemotherapy ✓ ✓ ✓ ✓ Discontinuation of chemotherapy ✓ ✓ ✓ ✓ Endpoints The primary endpoint is the incidence of grade ≥ 2 HFS within 3 months. Secondary endpoints include time to onset of grade ≥ 2 HFS, time to onset of grade ≥ 1 HFS within 3 months, incidences of dose reduction, schedule delay, discontinuation due to capecitabine-induced HFS, an incidence of grade ≥ 2 peripheral sensory neuropathy, and incidences of any grade capecitabine-related adverse events (nausea, vomiting, appetite loss, diarrhea, oral mucositis, pigmentation, abnormality of liver and renal functions, and neutropenia). Sample size calculation Based on previous RCTs evaluating the preventive effect for HFS, the incidence of grade ≥ 2 HFS within 3 months in the control group without preventive measures was approximately 40% [ 19 , 20 , 36 ]. Accordingly, the incidence of grade ≥ 2 HFS in the placebo arm is assumed to be 40%. It is expected that diclofenac sodium 0.1% cream will suppress grade ≥ 2 HFS within 3 months by 15%, resulting in an anticipated incidence rate of 25%. With a power of 80% and one-sided α of 5%, the required sample size is 160 patients in each arm. Therefore, the target number of enrolled patients is 320. No interim analysis is planned. Sample size calculations will be performed using SAS Studio 3.8. Discussion This study investigates the preventive effect of topical diclofenac sodium 0.1% cream for capecitabine-induced HFS. According to the Common Terminology Criteria for Adverse Events version 5.0, grade 2 HFS is defined as a painful skin change, including delamination, blistering, and bleeding, which significantly reduces patients’ QOL. It often leads to treatment interruption, dose reduction, or even discontinuation of capecitabine. Preventing grade ≥ 2 HFS is expected not only improve patients’ QOL but also maintain treatment intensity. As reducing the overall incidence of HFS is more clinically meaningful than merely delaying its onset, the incidence of grade ≥ 2 HFS within 3 months is set as the primary endpoint. The evaluation period is set at 3 months because, in patients receiving eight courses (6 months) of capecitabine plus oxaliplatin as adjuvant chemotherapy after surgery of colorectal cancer, the incidence of HFS increased until the 4th course (at 3 months after the start of treatment) and then plateaued [ 37 ]. In addition, the median time of onset of grade ≥ 2 HFS induced by fluoropyrimidine anticancer drugs has been reported to be approximately 100 days [ 38 , 39 ]. Therefore, evaluating the incidence of grade ≥ 2 HFS at 3 months is deemed appropriate as the primary endpoint. The majority of participants are expected to be patients with colorectal cancer, receiving capecitabine as adjuvant chemotherapy, which is typically recommended for at least 4 courses (3 months). In Japan, capecitabine plus oxaliplatin in combination with bevacizumab is the most commonly used palliative chemotherapy, with a reported median progression free survival time of approximately 10 months [ 39 ]. The second major population will consist of patients with breast cancer. The median progression-free survival of capecitabine monotherapy in patients with advanced breast cancer has been reported as approximately 3.2 months [ 7 ]. Thus, it is expected that most participants will continue capecitabine for 3 months, facilitating the evaluation of the primary endpoint. The expectation of a 15% reduction in the frequency of HFS is based on a study using celecoxib as the study drug, where the incidence of grade ≥ 2 HFS was reduced by approximately 20% compared with the placebo group [ 19 , 20 ]. Based on these reports, we expect that a 15% reduction in incidence of HFS would provide a lower risk and equally effective preventive method compared to celecoxib. The secondary endpoints include the time to onset of grade ≥ 2 HFS, the time to onset of grade ≥ 1 HFS within 3 months, incidences of dose reduction, schedule delay, discontinuation due to capecitabine-induced HFS, an incidence of grade ≥ 2 peripheral sensory neuropathy, and an incidence of any grade capecitabine-related adverse events (nausea, vomiting, appetite loss, diarrhea, oral mucositis, pigmentation, abnormality of liver and renal functions, and neutropenia). It is anticipated that preventing HFS with diclofenac cream may improve the dose intensity of capecitabine. However, there is a concern that capecitabine-related adverse events (nausea, vomiting, anorexia, diarrhea, mucositis, pigmentation, liver dysfunction, renal dysfunction, myelosuppression) may be exacerbated. Peripheral sensory neuropathy is also included as a secondary endpoint, assuming that absence of grade ≥ 2 HFS may alleviate some symptoms of neuropathy induced by oxaliplatin. The stratification factors for randomization include the dose of capecitabine and sex, as the incidence of HFS depends on capecitabine dose. Additionally, capecitabine-related adverse events differ between sexes [ 40 , 41 ]. Body composition also varies between women and men [ 42 , 43 ]. A previous study showed that female patients with colorectal cancer experienced more dose-limiting toxicity than male patients when capecitabine was administered based on body surface area [ 41 ] (Fig. 1 ). If the J-DIRECT study demonstrates the prophylactic efficacy of diclofenac sodium 0.1% cream against capecitabine-induced HFS, it could establish a new preventive therapy for HFS. In addition, the suppression of HFS with topical diclofenac cream may improve the efficacy of high-dose intensity capecitabine-based chemotherapy. Abbreviations CAPEOX Capecitabine plus intravenous oxaliplatin FOLFOX 5-Fluorouracil and leucovorin plus oxaliplatin HFS Hand-foot syndrome jRCT Japan Registry of Clinical Trials QOL Quality of life RCT Randomized controlled trial. Declarations Acknowledgements We especially thank Dr. Hiroshi Ishiguro, Dr. Hironobu Hashimoto, Dr. Sadamoto Zenda and Dr. Keita Mori on behalf of Japan Supportive, Palliative and Psychosocial Oncology Group (J-SUPPORT) for contributing on the constructing study protocol. We also thank all the physicians, nurses, research assistants and patient groups who contributed to the planning of this study. In addition, we thank to Kayoko Yoshida who created illustrations of palms and sole for self-report table. Author contributions YI conceived the idea presented in this study, and NB, HH, HI revised the study design. MN and SO created the statistical settings for this study. YI, HI, HH, MN, SO, KA, AK, SH, NF, TY, SZ, HM, and NB developed the theory. All authors discussed the results and contributed to the final manuscript. All authors read and approved the final manuscript. Funding This work was supported by a Practical Research for Innovative Cancer Control project grant (No. 24ck0106978h0001) from the Japan Agency for Medical Research. Availability of data and materials The data that support the findings of this study are available from the corresponding author, YI, upon reasonable request. Ethics approval and consent to participate This protocol was reviewed and approved by the certified Clinical Research Review Board of the University of Tokyo (approval number: 2024505SP) prior to conducting the trial. This clinical trial was conducted in compliance with the Clinical Trials Act in Japan and was registered in the Japan Registry of Clinical Trials (jRCT) as jRCTs031240705. All patients were required to provide written informed consent. Participating institutions The IMSUT Hospital, The Institute of Medical Science, The University of Tokyo (Tokyo), NTT Medical Center Tokyo (Tokyo), Aomori Prefectural Central Hospital (Aomori), Jyoban Hospital, Tokiwa Foundation (Fukushima), Seirei Hamamatsu General Hospital (Shizuoka), Gifu University Hospital (Gifu), Kawakita General Hospital Annex (Tokyo), St. Marianna University School of Medicine Hospital (Kanagawa), National Cancer Center Hospital (Tokyo), Yokohama City Minato Red Cross Hospital (Kanagawa), Kyoto University Hospital (Kyoto), Kurashiki Central Hospital (Okayama), Tokyo Metropolitan Police Hospital (Tokyo), Aichi Cancer Center (Aichi), Teine Keijinkai Hospital (Hokkaido), Mie University Hospital (Mie), Ageo Central General Hospital (Saitama), Saitama Medical Center (Saitama) Consent for publication Not applicable. Competing interests Hiroshi Ishiguro received a research grant from AstraZenecaKK, ONO PHARMACEUTICAL CO., LTD., DAIICHI SANKYO COMPANY, LIMITED, CHUGAI PHARMACEUTICAL CO., LTD., NIPRO CORPORATION, Takeda Pharmaceutical Co., Ltd., MSD K.K., Eisai Co., Ltd.; Narikazu Boku received lecture fees from Bristol Myers Squibb, Eli Lilly & Co., TAIHO PHARMACEUTICAL, CO., LTD., Astellas Pharma Inc.; Yohei Iimura, Hironobu Hashimoto, Masanori Nojima, Shunsuke Oyamada, Keita Mori, Keisuke Ariyoshi, Seiichiro Kuroda, Satoshi Hirakawa, Noriko Fujiwara, Tomoya Yokota, Sadamoto Zenda, Hiromichi Matsuoka has no conflict of interest. Confidentiality Personal information such as name, address, and medical ID will be not collected. Access to data Only clinical data managers at the central data center have access to reported case data through the EDC system during the study period. The data manager will transfer the final data set to the principal investigator and the data will be stored in the electronic format. Trial status The study will be initiated in April 2025. We expect to complete the recruitment by March 2027. References Sibaud V, Dalenc F, Chevreau C. et al . HFS-14, a specific quality of life scale developed for patients suffering from hand-foot syndrome. Oncologist 2011; 16 :1469–78. Grothey A, Sobrero AF, Shields AF et al . Duration of Adjuvant Chemotherapy for Stage III Colon Cancer. N Engl J Med 2018; 378 :1177–88. Yamazaki K, Yamanaka T, Shiozawa M. et al . Oxaliplatin-based adjuvant chemotherapy duration (3 versus 6 months) for high-risk stage II colon cancer: the randomized phase III ACHIEVE-2 trial. Ann Oncol 2021; 32 :77–84. Hamaguchi T, Shimada Y, Mizusawa J. et al . Capecitabine versus S-1 as adjuvant chemotherapy for patients with stage III colorectal cancer (JCOG0910): an open-label, non-inferiority, randomised, phase 3, multicentre trial. Lancet Gastroenterol Hepatol 2018; 3 :47–56. Masuda N, Lee SJ, Ohtani S. et al . Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. N Engl J Med 2017; 376 :2147–59. Geyer CE, Forster J, Lindquist D et al . Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006; 355 :2733–43. Blum JL, Dieras V, Lo Russo PM. et al . Multicenter, Phase II study of capecitabine in taxane-pretreated metastatic breast carcinoma patients. Cancer 2001; 92 :1759–68. Bang YJ, Van Cutsem E, Feyereislova A. et al . Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010; 376 :687–97. Cunningham D, Starling N, Rao S. et al . Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 2008; 358 :36–46. Yamaguchi K, Sawaki A, Doi T. et al . Efficacy and safety of capecitabine plus cisplatin in Japanese patients with advanced or metastatic gastric cancer: subset analyses of the AVAGAST study and the ToGA study. Gastric Cancer 2013; 16 :175–82. Yokokawa T, Kawakami K, Mae Y. et al . Risk factors exacerbating hand-foot skin reaction induced by capecitabine plus oxaliplatin with or without bevacizumab therapy. Ann Pharmacother 2015;49:1120–4. Leicher LW, de Graaf JC, Coers W. et al . Tolerability of capecitabine monotherapy in metastatic colorectal cancer: A real-world study. Drugs R D 2017; 17 :117–24. Lakkunarajah S, Breadner DA, Zhang H. et al . The influence of adjuvant chemotherapy dose intensity on five-year outcomes in resected colon cancer: A single centre retrospective analysis. Curr Oncol 2021; 28 :4031–41. Scheithauer W, Blum J. Coming to grips with hand-foot syndrome. Insights from clinical trials evaluating capecitabine. Oncology (Williston Park) 2004; 18 :1161–8, 1173;discussion 1173–66, 1181–64. Degen A, Alter M, Schenck F. et al . The hand-foot-syndrome associated with medical tumor therapy - classification and management. J Dtsch Dermatol Ges 2010; 8 :652–61. Hofheinz RD, Gencer D, Schulz H. et al . Mapisal versus urea cream as prophylaxis for capecitabine-associated hand-foot syndrome: A randomized phase III trial of the AIO quality of life working group. J Clin Oncol 2015; 33 :2444–9. Wolf SL, Qin R, Menon SP. et al . Placebo-controlled trial to determine the effectiveness of a urea/lactic acid-based topical keratolytic agent for prevention of capecitabine-induced hand-foot syndrome: North Central Cancer Treatment Group Study N05C5. J Clin Oncol 2010; 28 :5182–7. Lu W, Huang Z, Chen S. et al . The effectiveness of EVOSKIN®Palm and sole moisturizing cream in treating capecitabine-associated hand-foot syndrome: a randomized double-blind clinical trial. Ann Palliat Med 2021; 10 :3009–17. Zhang RX, Wu XJ, Lu SX. et al . The effect of COX-2 inhibitor on capecitabine-induced hand-foot syndrome in patients with stage II/III colorectal cancer: a phase II randomized prospective study. J Cancer Res Clin Oncol 2011; 137 :953–7. Zhang RX, Wu XJ, Wan DS. et al . Celecoxib can prevent capecitabine-related hand-foot syndrome in stage II and III colorectal cancer patients: result of a single-center, prospective randomized phase III trial. Ann Oncol 2012; 23 :1348–53. Yamamoto D, Yamamoto C, Iwase S. et al . Efficacy of vitamin E treatment for hand-foot syndrome in patients receiving capecitabine. Breast Care (Basel) 2010; 5 :415–6. Jo SJ, Shin H, Jo S et al . Prophylactic and therapeutic efficacy of pyridoxine supplements in the management of hand-foot syndrome during chemotherapy: a meta-analysis. Clin Exp Dermatol 2015; 40 :260–70. Son HS, Lee WY, Lee WS. et al . Compliance and effective management of the hand-foot syndrome in colon cancer patients receiving capecitabine as adjuvant chemotherapy. Yonsei Med J 2009; 50 :796–802. Van Cutsem E, Twelves C, Cassidy J. et al . Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol 2001; 19 :4097–106. Blum JL, Jones SE, Buzdar AU. et al . Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 1999; 17 :485–93. Lacouture ME, Sibaud V, Gerber PA. et al . Prevention and management of dermatological toxicities related to anticancer agents: ESMO Clinical Practice Guidelines(☆). Ann Oncol 2021;32:157–70. Diasio RB. Oral DPD-inhibitory fluoropyrimidine drugs. Oncology (Williston Park) 2000;14:19–23. Yokomichi N, Nagasawa T, Coler-Reilly A. et al . Pathogenesis of hand-foot syndrome induced by PEG-modified liposomal doxorubicin. Hum Cell 2013; 26 :8–18. Iimura Y, Furukawa N, Ishibashi M. et al . Study protocol of a single-arm phase 2 study evaluating the preventive effect of topical hydrocortisone for capecitabine-induced hand-foot syndrome in colorectal cancer patients receiving adjuvant chemotherapy with capecitabine plus oxaliplatin (T-CRACC study). BMC Gastroenterol 2022; 22 :341. Santhosh A, Kumar A, Pramanik R et al . Randomized double-blind, placebo-controlled study of topical diclofenac in the prevention of hand-foot syndrome in patients receiving capecitabine (the D-TORCH study). Trials 2022; 23 :420. Drake RD, Lin WM, King M. et al . Oral dexamethasone attenuates Doxil-induced palmar-plantar erythrodysesthesias in patients with recurrent gynecologic malignancies. Gynecol Oncol 2004; 94 :320–4. Brown J, Burck K, Black D, Collins C. Treatment of cytarabine acral erythema with corticosteroids. J Am Acad Dermatol 1991; 24 :1023–5. Hoff PM, Valero V, Ibrahim N. et al . Hand-foot syndrome following prolonged infusion of high doses of vinorelbine. Cancer 1998; 82 :965–9. Lin E, Morris JS, Ayers GD. Effect of celecoxib on capecitabine-induced hand-foot syndrome and antitumor activity. Oncology (Williston Park) 2002; 16 :31–7. Santhosh A, Sharma A, Bakhshi S. et al . Topical diclofenac for prevention of capecitabine-associated hand-foot syndrome: A double-blind randomized controlled trial. J Clin Oncol 2024;42:1821–9. Ostwal V, Kapoor A, Mandavkar S et al . Effect of a structured teaching module including intensive prophylactic measures on reducing the incidence of capecitabine-induced hand-foot syndrome: Results of a prospective randomized phase III study. Oncologist 2020; 25 :e1886–92. Danno K, Hata T, Tamai K. et al . Interim analysis of a phase II trial evaluating the safety and efficacy of capecitabine plus oxaliplatin (XELOX) as adjuvant therapy in Japanese patients with operated stage III colon cancer. Cancer Chemother Pharmacol 2017; 80 :777–85. Twelves C, Wong A, Nowacki MP. et al . Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 2005; 352 :2696–704. Cassidy J, Clarke S, Díaz-Rubio E et al . Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 2008; 26 :2006–12. Jiang Y, Mason M, Cho Y. et al . Tolerance to oral anticancer agent treatment in older adults with cancer: a secondary analysis of data from electronic health records and a pilot study of patient-reported outcomes. BMC Cancer 2022; 22 :950. Ilich AI, Danilak M, Kim CA. et al . Effects of gender on capecitabine toxicity in colorectal cancer. J Oncol Pharm Pract 2016; 22 :454–60. Özdemir BC, Gerard CL, Espinosa da Silva C. Sex and gender differences in anticancer treatment toxicity: A call for revisiting drug dosing in oncology. Endocrinology 2022; 163 . Wagner AD. Sex differences in cancer chemotherapy effects, and why we need to reconsider BSA-based dosing of chemotherapy. ESMO Open 2020;5:e000770. Kang YK, Lee SS, Yoon DH. et al . Pyridoxine is not effective to prevent hand-foot syndrome associated with capecitabine therapy: results of a randomized, double-blind, placebo-controlled study. J Clin Oncol 2010; 28 :3824–9. Ota M, Tatsumi K, Suwa H. et al . The effect of pyridoxine for prevention of hand-foot syndrome in colorectal cancer patients with adjuvant chemotherapy using capecitabine: A randomized study. Hepatogastroenterology 2014; 61 :1008–13. Yap YS, Kwok LL, Syn N et al . Predictors of hand-foot syndrome and pyridoxine for prevention of capecitabine-induced hand-foot syndrome: A randomized clinical trial. JAMA Oncol 2017; 3 :1538–45. Toyama T, Yoshimura A, Hayashi T. et al . A randomized phase II study evaluating pyridoxine for the prevention of hand-foot syndrome associated with capecitabine therapy for advanced or metastatic breast cancer. Breast Cancer 2018; 25 :729–35. Watanabe K, Ishibe A, Watanabe J. et al . The effect of TJ-28 (Eppikajutsuto) on the prevention of hand-foot syndrome using capecitabine for colorectal cancer: The Yokohama Clinical Oncology Group Study (YCOG1102). Indian J Gastroenterol 2020; 39 :204–10. Table 3 Table 3 is available in the Supplementary Files section. Supplementary Files Table3.docx Cite Share Download PDF Status: Published Journal Publication published 14 May, 2025 Read the published version in International Journal of Clinical Oncology → Version 1 posted Editorial decision: Minor revisions 20 Apr, 2025 Reviewers agreed at journal 30 Mar, 2025 Reviewers invited by journal 30 Mar, 2025 Editor assigned by journal 26 Mar, 2025 First submitted to journal 24 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6299256","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":435886739,"identity":"759c249b-96ab-40b0-9ebe-cf04fe73ae24","order_by":0,"name":"Yohei Iimura","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9UlEQVRIiWNgGAWjYJCCwz8MbBgMGBgbHwA5PHxE6GB8zFCQBtLSbADSwkaEFmZjhg+HgVoY2CRAXIJaDI43sEkXGBxmMGdvbqv8mmMnw8bA/PDRDXxazhxgk55hkM5g2XOw7bbstmSgw9iMjXPwabmRwCbBY2ANZCS23ZbcxgzUwsMmTYQWZgaD+w/biiW31ROlhdmYx8AZyGBsY/y47TBhLZJnDjY+nGGQxmNwJrFZmnHbcR42ZgJ+4TvefODAhz82cgbHjz/8+HNbtT0/e/PDx/i0KBxgbADRPCCCGULiUQ4C8g1IHMYfBFSPglEwCkbByAQArjxHOsNvcm0AAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-3473-8244","institution":"The University of Tokyo: Tokyo Daigaku","correspondingAuthor":true,"prefix":"","firstName":"Yohei","middleName":"","lastName":"Iimura","suffix":""},{"id":435886740,"identity":"ca2528d2-fae7-4f85-8ac2-477de10126a0","order_by":1,"name":"Hiroshi Ishiguro","email":"","orcid":"","institution":"Saitama Medical University International Medical Center: Saitama Ika Daigaku Kokusai Iryo Center","correspondingAuthor":false,"prefix":"","firstName":"Hiroshi","middleName":"","lastName":"Ishiguro","suffix":""},{"id":435886741,"identity":"d8532e25-b768-4421-b72f-e4fcdad2fd13","order_by":2,"name":"Hironobu Hashimoto","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Hironobu","middleName":"","lastName":"Hashimoto","suffix":""},{"id":435886742,"identity":"2d7a8607-5180-4ebf-a026-f39eb0e298b4","order_by":3,"name":"Masanori Nojima","email":"","orcid":"","institution":"The University of Tokyo: Tokyo Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Masanori","middleName":"","lastName":"Nojima","suffix":""},{"id":435886743,"identity":"fec06cd2-3a51-42bc-8783-5b59d82e37be","order_by":4,"name":"Shunsuke Oyamada","email":"","orcid":"","institution":"JORTC","correspondingAuthor":false,"prefix":"","firstName":"Shunsuke","middleName":"","lastName":"Oyamada","suffix":""},{"id":435886744,"identity":"5ea89bfd-0fe8-4e9f-9c04-11428ff9e9a7","order_by":5,"name":"Keita Mori","email":"","orcid":"","institution":"Shizuoka Cancer Center: Shizuoka Kenritsu Shizuoka Gan Center","correspondingAuthor":false,"prefix":"","firstName":"Keita","middleName":"","lastName":"Mori","suffix":""},{"id":435886745,"identity":"6a99f659-4981-4b61-b01a-0f44d37c35c0","order_by":6,"name":"Keisuke Ariyoshi","email":"","orcid":"","institution":"JORC","correspondingAuthor":false,"prefix":"","firstName":"Keisuke","middleName":"","lastName":"Ariyoshi","suffix":""},{"id":435886746,"identity":"2b06315e-e4a4-4c88-8331-96a92bcea844","order_by":7,"name":"Seiichiro Kuroda","email":"","orcid":"","institution":"The University of Tokyo: Tokyo Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Seiichiro","middleName":"","lastName":"Kuroda","suffix":""},{"id":435886747,"identity":"040209de-a0e6-4fe9-9d02-b60547541ab7","order_by":8,"name":"Satoshi Hirakawa","email":"","orcid":"","institution":"Seirei Hamamatsu Hospital: Seirei Hamamatsu Byoin","correspondingAuthor":false,"prefix":"","firstName":"Satoshi","middleName":"","lastName":"Hirakawa","suffix":""},{"id":435886748,"identity":"20ac642c-fb31-4308-a63e-3d01d98fc7ff","order_by":9,"name":"Noriko Fujiwara","email":"","orcid":"","institution":"The University of Tokyo: Tokyo Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Noriko","middleName":"","lastName":"Fujiwara","suffix":""},{"id":435886749,"identity":"494e11ca-560b-4862-921f-750687f902c6","order_by":10,"name":"Tomoya Yokota","email":"","orcid":"","institution":"Shizuoka Cancer Center: Shizuoka Kenritsu Shizuoka Gan Center","correspondingAuthor":false,"prefix":"","firstName":"Tomoya","middleName":"","lastName":"Yokota","suffix":""},{"id":435886750,"identity":"ffe25c1b-9943-4a55-a5a6-a4cae4905b70","order_by":11,"name":"Sadamoto Zenda","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Sadamoto","middleName":"","lastName":"Zenda","suffix":""},{"id":435886751,"identity":"8cc50918-573a-4413-b3d9-38e5add19920","order_by":12,"name":"Hiromichi Matsuoka","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Hiromichi","middleName":"","lastName":"Matsuoka","suffix":""},{"id":435886752,"identity":"f9fb61e1-2076-4de4-a9e4-5002020c81d2","order_by":13,"name":"Narikazu Boku","email":"","orcid":"","institution":"The University of Tokyo: Tokyo Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Narikazu","middleName":"","lastName":"Boku","suffix":""}],"badges":[],"createdAt":"2025-03-25 02:28:39","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6299256/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6299256/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10147-025-02789-z","type":"published","date":"2025-05-14T15:57:18+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":81022986,"identity":"7880d772-5c1e-4910-8591-cfaf8f5f6cb4","added_by":"auto","created_at":"2025-04-21 10:06:19","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":47255,"visible":true,"origin":"","legend":"\u003cp\u003eStudy scheme\u003c/p\u003e\n\u003cp\u003eRandomization will be conducted using a minimization method, adjusting for sex (male vs. female) and planned dose of capecitabine ([1] ≥ 800 mg/m\u003csup\u003e2\u003c/sup\u003e, \u0026lt; 1000mg/m\u003csup\u003e2\u003c/sup\u003e, [2] ≥ 1000, \u0026lt; 1250 mg/m\u003csup\u003e2\u003c/sup\u003e, [3] ≥ 1250 mg/m\u003csup\u003e2\u003c/sup\u003e). Topical hydrocortisone butyrate 0.1%, diclofenac sodium 0.1% cream, or placebo cream will be applied to the palms and soles daily in the morning and evening for 3 months. To maintain self-adherence, all patients will receive standard self-care education at the start of chemotherapy, and the number of study agents used regularly by clinical pharmacists will be confirmed. Clinical pharmacists will regularly educate patients to improve their adherence to intervention protocols.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6299256/v1/26ae4d5233ec95b7bf689bfc.jpg"},{"id":83068018,"identity":"63c1ab59-1500-43cf-bf7c-5a350b5a9b84","added_by":"auto","created_at":"2025-05-19 16:09:21","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":894655,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6299256/v1/c4c314d9-ec33-4eea-8134-c46d72b432f8.pdf"},{"id":81022985,"identity":"792b7ddd-723a-44c9-bd46-1467e30954dd","added_by":"auto","created_at":"2025-04-21 10:06:19","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":33474,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.docx","url":"https://assets-eu.researchsquare.com/files/rs-6299256/v1/ed4e7dedc71b46c89af4811a.docx"}],"financialInterests":"","formattedTitle":"A randomized, double-blind, placebo-controlled phase III study evaluating the preventive effect of diclofenac cream on capecitabine-related hand-foot syndrome: Study protocol of J-SUPPORT2401/JORTC-SUP06 (J-DIRECT)","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHand-foot syndrome (HFS) is the most common adverse event induced by capecitabine, often deteriorating patient\u0026rsquo;s quality of life (QOL) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In randomized controlled trials (RCTs) of systemic chemotherapy for colorectal cancer, the incidence of any grade HFS caused by capecitabine have been reported to be approximately 30\u0026ndash;80% [\u003cspan additionalcitationids=\"CR3 CR4 CR5 CR6 CR7 CR8 CR9\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], whereas real-world data suggest it is over 90% [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Severe HFS causes symptoms such as swelling, blisters, desquamation, and ulcers, often leading to treatment interruptions, delays in the treatment schedule, dose reduction, and discontinuation of capecitabine. One study showed that 17\u0026ndash;24% of patients with metastatic colorectal cancer receiving capecitabine monotherapy required dose and schedule modifications due to HFS [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Additionally, while it has been reported that dose intensity of capecitabine influences the outcomes of adjuvant chemotherapy for colon cancer [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], moderate or severe HFS requires treatment modifications (interruption and/or dose reduction) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Therefore, managing HFS is crucial not only for maintaining patient\u0026rsquo;s QOL but also for ensuring the therapeutic efficacy of capecitabine [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, a standard preventive therapy has not been established due to inconsistent results regarding the effectiveness of topical urea [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], exfoliating agents [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], celecoxib [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], vitamin E [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], and pyridoxine [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] for HFS. Currently, moisturizing and avoiding local pressure [\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] are recommended as standard management methods for preventing capecitabine-induced HFS [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe mechanism of HFS involves the inhibition of the skin basal cell proliferation, drug secretion from the eccrine sweat glands, the involvement of drug degradation products [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], and an inflammatory response triggered by interleukin (IL)-1a, IL-1b, IL-6, and reactive oxygen species [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Based on this rationale, a large phase III study demonstrated that celecoxib has a preventive effect on HFS. However, its clinical use has been limited because of concerns about adverse events caused by the long-term use of non-steroidal anti-inflammatory drugs (NSAIDs). Moreover, clinical trials have evaluated the preventive effects of medium-class topical steroids [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] and topical diclofenac [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Corticosteroids exert their anti-inflammatory effects by inhibiting the release of chemical mediators. Oral dexamethasone (8 mg/day, followed by tapering) was administered to patients with pegylated liposomal doxorubicin-induced HFS in a prospective study [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], which reported that patients receiving dexamethasone required fewer treatment modifications, such as schedule delays or dose reductions than those not receiving dexamethasone. Other case reports have suggested that corticosteroids may be effective against cytarabine-and vinorelbine-induced HFS [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. NSAIDs inhibit the production of cyclooxygenase (COX)-2, which is believed to contribute to the development of HFS [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Thus, anti-inflammatory agents may help prevent HFS caused by cytotoxic anti-tumor agents. Although the effectiveness of oral COX-2 inhibitors has been reported [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], safety concerns remain.\u003c/p\u003e \u003cp\u003eSince topical formulations offer better safety by reducing the systemic effects of NSAIDs, the topical use of anti-inflammatory agents such as corticosteroids and NSAIDs is expected to prevent HFS without major safety concerns. Recently, the preventive efficacy of topical diclofenac was reported in India (D-TORCH study) [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], demonstrating that the prophylactic administration of topical diclofenac reduced the frequency of grade\u0026thinsp;\u0026ge;\u0026thinsp;2 HFS by 11.2% (3.8% vs 15.0%). However, the incidence of HFS in the placebo group of the D-TORCH study was substantially lower than that in other Asian studies (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Additionally, the D-TORCH study evaluated the effectiveness of topical diclofenac only on the hands, not the soles. Furthermore, while the study used a diclofenac gel base, the isopropanol in the gel may cause skin dryness and irritation, potentially worsening HFS symptoms. A cream based formulation is generally considered more suitable than a gel for preventing HFS.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDifference of the incidence of HFS induced by capecitabine in India (D-TORCH study) and other Asian countries in randomized controlled trials\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"11\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eIncidence rate of HFS (any grade)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003eIncidence rate of HFS (grade 2 or 3)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003eIncidence rate of HFS (\u0026ge;\u0026thinsp;grade 3)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eNumber of patients\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCountry\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIntervention\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBlind\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIntervention\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIntervention\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eIntervention\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eIntervention\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChina 2010\u003c/p\u003e \u003cp\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCelecoxib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e11.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChina 2012\u003c/p\u003e \u003cp\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCelecoxib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e57.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e74.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e14.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e29.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e8.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSouth Korea 2010\u003c/p\u003e \u003cp\u003e[\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePyridoxine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e180\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e180\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e76.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e15.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e3.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJapan 2014\u003c/p\u003e \u003cp\u003e[\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePyridoxine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSingapore 2017\u003c/p\u003e \u003cp\u003e[\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePyridoxine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e105\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e105\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJapan 2018\u003c/p\u003e \u003cp\u003e[\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePyridoxine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJapan 2020\u003c/p\u003e \u003cp\u003e[\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEppikajutsuto (Kampo medicine)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e83.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e8.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChina 2021\u003c/p\u003e \u003cp\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLithium containing topical and moisturizing cream\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e56.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e75.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e16.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e6.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e16.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIndia 2020\u003c/p\u003e \u003cp\u003e[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStructured teaching module\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e135\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e134\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e64.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e62.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e33.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e32.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e5.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e6.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIndia 2024\u003c/p\u003e \u003cp\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTopical diclofenac\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e130\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e133\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e18.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e5.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThis multicenter, randomized, double-blind, placebo-controlled, phase 3 trial aims to confirm the preventive effect of diclofenac sodium 0.1% cream for capecitabine-induced HFS.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThis is a multicenter, randomized, double-blind, placebo-controlled, phase 3 study. The study protocol was reviewed and approved by the certified Clinical Research Review Board of the University of Tokyo (approval number 2024505SP). The study is being conducted in compliance with the Clinical Trials Act in Japan and registered in the Japan Registry of Clinical Trials (jRCT) as jRCTs031240705.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eParticipants\u003c/h3\u003e\n\u003cp\u003eThe following patients are included in this study: (i) patients with colorectal, breast, or gastric cancer planned to receive chemotherapy containing capecitabine (\u0026ge;\u0026thinsp;800 mg/m\u003csup\u003e2\u003c/sup\u003e); (ii) Eastern Cooperative Oncology Group performance status of 0\u0026ndash;1, (iii) aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years; and (iv) providing written informed consent. Exclusion criteria are as follows: (i) history of aspirin-induced asthma; (ii) presence of other skin diseases, skin lesions due to chemotherapy on the palms or soles, or dermatitis that makes it difficult to evaluate the efficacy of the study drug; (iii) history of hypersensitivity to local diclofenac; (iv) conditions requiring the constant use of steroids or NSAIDs; (v) scheduled to receive other anti-tumor agents (e.g. multi kinase inhibitors for anti-angiogenesis) that may interfere with the evaluation of efficacy of the study drug; (vii) pregnancy, breast feeding, or inablility to adhere to contraception during the study period; and (viii) sensory palsy in the palms or soles.\u003c/p\u003e\n\u003ch3\u003eRandomization\u003c/h3\u003e\n\u003cp\u003eAfter confirming eligibility, patients are registered using an independent central registration system. They are randomized in a 1:1 ratio to receive either diclofenac sodium 0.1% cream or a placebo cream using the minimization method, adjusted for sex (male vs. female), planned dose of capecitabine (\u0026ge;\u0026thinsp;800 mg/m\u003csup\u003e2\u003c/sup\u003e, \u0026lt; 1000 mg/m\u003csup\u003e2\u003c/sup\u003e, \u0026ge; 1000, \u0026lt; 1250 mg/m\u003csup\u003e2\u003c/sup\u003e, \u0026ge; 1250 mg/m\u003csup\u003e2\u003c/sup\u003e), and participating institution.\u003c/p\u003e\n\u003ch3\u003eChemotherapy\u003c/h3\u003e\n\u003cp\u003eCombination with other anti-tumor agents (e.g. oxaliplatin) and radiation (except for the palms and soles) is allowed if it includes capecitabine (\u0026ge;\u0026thinsp;800 mg/m\u003csup\u003e2\u003c/sup\u003e). However, multi-kinase inhibitors (e.g., lapatinib) will not be allowed. Dose interruptions, delays, reductions, and discontinuations are allowed at each physician\u0026rsquo;s discretion.\u003c/p\u003e\n\u003ch3\u003eIntervention\u003c/h3\u003e\n\u003cp\u003eBoth diclofenac sodium 0.1% cream and placebo are white cream products. The hydrophilic cream, which is the base material of diclofenac sodium 0.1% cream, is selected as the placebo. Since there is no noticeable difference in appearance or odor, double-blindness is ensured. Topical diclofenac sodium 0.1% cream or placebo is applied to the palms and soles twice daily in the morning and evening. More than one fingertip unit (one fingertip unit provides 0.5 g) of the study drug is applied to each palm and sole. This preventive treatment is initiated in the evening on day 1 and continued throughout the study period. All patients receive standard self-care education (e.g., maintaining cleanliness, avoiding strenuous exercise and pressure, and using sun protection) at the start of chemotherapy. Clinical pharmacists monitor the volume of study drugs used by checking the remaining amount and educate the patients to improve their adherence, if necessary.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eProhibited therapy and drugs\u003c/h2\u003e \u003cp\u003eThe following treatments or concomitant use of drugs are prohibited: (i) cancer treatment other than the capecitabine-based chemotherapy (localized radiation therapy excluding the palm or sole is allowed), (ii) continuous use of other topical corticosteroids or NSAIDs on the palms or soles, (iii) continuous use of NSAIDs, (iv) continuous use of pyridoxine, (v) use of multi-kinase inhibitors.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eDiscontinuation of interventions\u003c/h3\u003e\n\u003cp\u003eInterventions are discontinued if any of the following events occurs: (i) discontinuation of capecitabine for any reason, (ii) withdrawal of consent, (iii) serious adverse events induced by the study drugs, and (iv) use of prohibited therapies or drugs. Optimal medical care without the study drugs is guaranteed to participants who discontinue or deviate from the intervention protocols.\u003c/p\u003e\n\u003ch3\u003eEvaluation\u003c/h3\u003e\n\u003cp\u003ePatients complete a self-report check sheet daily to document symptoms of HFS and adherence to the study drug. Patient\u0026rsquo;s symptoms and laboratory tests results are reviewed at every visit, and the severity of HFS is assessed by the clinical pharmacist and attending physician by referring to the self-reported adverse events (Tables\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Evaluators will be undergo regular training to ensure data quality.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAssessment schedule\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c7\" namest=\"c4\"\u003e \u003cp\u003eChemotherapy period (weeks)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePretreatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePerformance status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eBlood test\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eHand-foot syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePeripheral sensory neuropathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eNausea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eVomiting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eAppetite loss\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eDiarrhea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eOral mucositis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePigmentation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eAbnormality of liver function\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eAbnormality of renal function\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eNeutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eSelf-report (adverse events)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eSelf-report (self-adherence)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eDose of chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePostponement of chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eDiscontinuation of chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eEndpoints\u003c/h2\u003e \u003cp\u003eThe primary endpoint is the incidence of grade\u0026thinsp;\u0026ge;\u0026thinsp;2 HFS within 3 months. Secondary endpoints include time to onset of grade\u0026thinsp;\u0026ge;\u0026thinsp;2 HFS, time to onset of grade\u0026thinsp;\u0026ge;\u0026thinsp;1 HFS within 3 months, incidences of dose reduction, schedule delay, discontinuation due to capecitabine-induced HFS, an incidence of grade\u0026thinsp;\u0026ge;\u0026thinsp;2 peripheral sensory neuropathy, and incidences of any grade capecitabine-related adverse events (nausea, vomiting, appetite loss, diarrhea, oral mucositis, pigmentation, abnormality of liver and renal functions, and neutropenia).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eSample size calculation\u003c/h2\u003e \u003cp\u003eBased on previous RCTs evaluating the preventive effect for HFS, the incidence of grade\u0026thinsp;\u0026ge;\u0026thinsp;2 HFS within 3 months in the control group without preventive measures was approximately 40% [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Accordingly, the incidence of grade\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;2 HFS in the placebo arm is assumed to be 40%. It is expected that diclofenac sodium 0.1% cream will suppress grade\u0026thinsp;\u0026ge;\u0026thinsp;2 HFS within 3 months by 15%, resulting in an anticipated incidence rate of 25%. With a power of 80% and one-sided α of 5%, the required sample size is 160 patients in each arm. Therefore, the target number of enrolled patients is 320. No interim analysis is planned. Sample size calculations will be performed using SAS Studio 3.8.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study investigates the preventive effect of topical diclofenac sodium 0.1% cream for capecitabine-induced HFS.\u003c/p\u003e \u003cp\u003eAccording to the Common Terminology Criteria for Adverse Events version 5.0, grade 2 HFS is defined as a painful skin change, including delamination, blistering, and bleeding, which significantly reduces patients\u0026rsquo; QOL. It often leads to treatment interruption, dose reduction, or even discontinuation of capecitabine. Preventing grade\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;2 HFS is expected not only improve patients\u0026rsquo; QOL but also maintain treatment intensity. As reducing the overall incidence of HFS is more clinically meaningful than merely delaying its onset, the incidence of grade\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;2 HFS within 3 months is set as the primary endpoint. The evaluation period is set at 3 months because, in patients receiving eight courses (6 months) of capecitabine plus oxaliplatin as adjuvant chemotherapy after surgery of colorectal cancer, the incidence of HFS increased until the 4th course (at 3 months after the start of treatment) and then plateaued [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. In addition, the median time of onset of grade\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;2 HFS induced by fluoropyrimidine anticancer drugs has been reported to be approximately 100 days [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Therefore, evaluating the incidence of grade\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;2 HFS at 3 months is deemed appropriate as the primary endpoint. The majority of participants are expected to be patients with colorectal cancer, receiving capecitabine as adjuvant chemotherapy, which is typically recommended for at least 4 courses (3 months). In Japan, capecitabine plus oxaliplatin in combination with bevacizumab is the most commonly used palliative chemotherapy, with a reported median progression free survival time of approximately 10 months [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. The second major population will consist of patients with breast cancer. The median progression-free survival of capecitabine monotherapy in patients with advanced breast cancer has been reported as approximately 3.2 months [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Thus, it is expected that most participants will continue capecitabine for 3 months, facilitating the evaluation of the primary endpoint.\u003c/p\u003e \u003cp\u003eThe expectation of a 15% reduction in the frequency of HFS is based on a study using celecoxib as the study drug, where the incidence of grade\u0026thinsp;\u0026ge;\u0026thinsp;2 HFS was reduced by approximately 20% compared with the placebo group [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Based on these reports, we expect that a 15% reduction in incidence of HFS would provide a lower risk and equally effective preventive method compared to celecoxib.\u003c/p\u003e \u003cp\u003eThe secondary endpoints include the time to onset of grade\u0026thinsp;\u0026ge;\u0026thinsp;2 HFS, the time to onset of grade\u0026thinsp;\u0026ge;\u0026thinsp;1 HFS within 3 months, incidences of dose reduction, schedule delay, discontinuation due to capecitabine-induced HFS, an incidence of grade\u0026thinsp;\u0026ge;\u0026thinsp;2 peripheral sensory neuropathy, and an incidence of any grade capecitabine-related adverse events (nausea, vomiting, appetite loss, diarrhea, oral mucositis, pigmentation, abnormality of liver and renal functions, and neutropenia). It is anticipated that preventing HFS with diclofenac cream may improve the dose intensity of capecitabine. However, there is a concern that capecitabine-related adverse events (nausea, vomiting, anorexia, diarrhea, mucositis, pigmentation, liver dysfunction, renal dysfunction, myelosuppression) may be exacerbated. Peripheral sensory neuropathy is also included as a secondary endpoint, assuming that absence of grade\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;2 HFS may alleviate some symptoms of neuropathy induced by oxaliplatin.\u003c/p\u003e \u003cp\u003eThe stratification factors for randomization include the dose of capecitabine and sex, as the incidence of HFS depends on capecitabine dose. Additionally, capecitabine-related adverse events differ between sexes [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Body composition also varies between women and men [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. A previous study showed that female patients with colorectal cancer experienced more dose-limiting toxicity than male patients when capecitabine was administered based on body surface area [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e] (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIf the J-DIRECT study demonstrates the prophylactic efficacy of diclofenac sodium 0.1% cream against capecitabine-induced HFS, it could establish a new preventive therapy for HFS. In addition, the suppression of HFS with topical diclofenac cream may improve the efficacy of high-dose intensity capecitabine-based chemotherapy.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCAPEOX\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCapecitabine plus intravenous oxaliplatin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFOLFOX\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e5-Fluorouracil and leucovorin plus oxaliplatin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHFS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHand-foot syndrome\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ejRCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eJapan Registry of Clinical Trials\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eQOL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eQuality of life\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRandomized controlled trial.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eWe especially thank Dr. Hiroshi Ishiguro, Dr. Hironobu Hashimoto, Dr. Sadamoto Zenda and Dr. Keita Mori on behalf of Japan Supportive, Palliative and Psychosocial Oncology Group (J-SUPPORT) for contributing on the constructing study protocol. We also thank all the physicians, nurses, research assistants and patient groups who contributed to the planning of this study. In addition, we thank to Kayoko Yoshida who created illustrations of palms and sole for self-report table.\u003c/p\u003e\n\u003cp\u003eAuthor contributions\u003c/p\u003e\n\u003cp\u003eYI conceived the idea presented in this study, and NB, HH, HI revised the study design. MN and SO created the statistical settings for this study. YI, HI, HH, MN, SO, KA, AK, SH, NF, TY, SZ, HM, and NB developed the theory. All authors discussed the results and contributed to the final manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis work was supported by a Practical Research for Innovative Cancer Control project grant (No. 24ck0106978h0001) from the Japan Agency for Medical Research.\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author, YI, upon reasonable request.\u003c/p\u003e\n\u003cp\u003eEthics approval and consent to participate This protocol was reviewed and approved by the certified Clinical Research Review Board of the University of Tokyo (approval number: 2024505SP) prior to conducting the trial. This clinical trial was conducted in compliance with the Clinical Trials Act in Japan and was registered in the Japan Registry of Clinical Trials (jRCT) as jRCTs031240705. All patients were required to provide written informed consent.\u003c/p\u003e\n\u003cp\u003eParticipating institutions\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe IMSUT Hospital, The Institute of Medical Science, The University of Tokyo (Tokyo), NTT Medical Center Tokyo (Tokyo), Aomori Prefectural Central Hospital (Aomori), Jyoban Hospital, Tokiwa Foundation (Fukushima), Seirei Hamamatsu General Hospital (Shizuoka), Gifu University Hospital (Gifu), Kawakita General Hospital Annex (Tokyo), St. Marianna University School of Medicine Hospital (Kanagawa), National Cancer Center Hospital (Tokyo), Yokohama City Minato Red Cross Hospital (Kanagawa), Kyoto University Hospital (Kyoto), Kurashiki Central Hospital (Okayama), Tokyo Metropolitan Police Hospital (Tokyo), Aichi Cancer Center (Aichi), Teine Keijinkai Hospital (Hokkaido), Mie University Hospital (Mie), Ageo Central General Hospital (Saitama), Saitama Medical Center (Saitama)\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eHiroshi Ishiguro received a research grant from AstraZenecaKK, ONO PHARMACEUTICAL CO., LTD., DAIICHI SANKYO COMPANY, LIMITED, CHUGAI PHARMACEUTICAL CO., LTD., NIPRO CORPORATION, Takeda Pharmaceutical Co., Ltd., MSD K.K., Eisai Co., Ltd.; Narikazu Boku received lecture fees from Bristol Myers Squibb, Eli Lilly \u0026amp; Co., TAIHO PHARMACEUTICAL, CO., LTD., Astellas Pharma Inc.; Yohei Iimura, Hironobu Hashimoto, Masanori Nojima, Shunsuke Oyamada, Keita Mori, Keisuke Ariyoshi, Seiichiro Kuroda, Satoshi Hirakawa, Noriko Fujiwara, Tomoya Yokota, Sadamoto Zenda, Hiromichi Matsuoka has no conflict of interest.\u003c/p\u003e\n\u003cp\u003eConfidentiality\u003c/p\u003e\n\u003cp\u003ePersonal information such as name, address, and medical ID will be not collected.\u003c/p\u003e\n\u003cp\u003eAccess to data\u003c/p\u003e\n\u003cp\u003eOnly clinical data managers at the central data center have access to reported case data through the EDC system during the study period. The data manager will transfer the final data set to the principal investigator and the data will be stored in the electronic format.\u003c/p\u003e\n\u003cp\u003eTrial status\u003c/p\u003e\n\u003cp\u003eThe study will be initiated in April 2025. We expect to complete the recruitment by March 2027.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSibaud V, Dalenc F, Chevreau C. \u003cem\u003eet al\u003c/em\u003e. HFS-14, a specific quality of life scale developed for patients suffering from hand-foot syndrome. Oncologist 2011;\u003cstrong\u003e16\u003c/strong\u003e:1469\u0026ndash;78.\u003c/li\u003e\n\u003cli\u003eGrothey A, Sobrero AF, Shields AF \u003cem\u003eet al\u003c/em\u003e. Duration of Adjuvant Chemotherapy for Stage III Colon Cancer. N Engl J Med 2018;\u003cstrong\u003e378\u003c/strong\u003e:1177\u0026ndash;88.\u003c/li\u003e\n\u003cli\u003eYamazaki K, Yamanaka T, Shiozawa M. \u003cem\u003eet al\u003c/em\u003e. Oxaliplatin-based adjuvant chemotherapy duration (3 versus 6 months) for high-risk stage II colon cancer: the randomized phase III ACHIEVE-2 trial. Ann Oncol 2021;\u003cstrong\u003e32\u003c/strong\u003e:77\u0026ndash;84.\u003c/li\u003e\n\u003cli\u003eHamaguchi T, Shimada Y, Mizusawa J. \u003cem\u003eet al\u003c/em\u003e. Capecitabine versus S-1 as adjuvant chemotherapy for patients with stage III colorectal cancer (JCOG0910): an open-label, non-inferiority, randomised, phase 3, multicentre trial. Lancet Gastroenterol Hepatol 2018;\u003cstrong\u003e3\u003c/strong\u003e:47\u0026ndash;56.\u003c/li\u003e\n\u003cli\u003eMasuda N, Lee SJ, Ohtani S. \u003cem\u003eet al\u003c/em\u003e. Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. N Engl J Med 2017;\u003cstrong\u003e376\u003c/strong\u003e:2147\u0026ndash;59.\u003c/li\u003e\n\u003cli\u003eGeyer CE, Forster J, Lindquist D \u003cem\u003eet al\u003c/em\u003e. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;\u003cstrong\u003e355\u003c/strong\u003e:2733\u0026ndash;43.\u003c/li\u003e\n\u003cli\u003eBlum JL, Dieras V, Lo Russo PM. \u003cem\u003eet al\u003c/em\u003e. Multicenter, Phase II study of capecitabine in taxane-pretreated metastatic breast carcinoma patients. Cancer 2001;\u003cstrong\u003e92\u003c/strong\u003e:1759\u0026ndash;68.\u003c/li\u003e\n\u003cli\u003eBang YJ, Van Cutsem E, Feyereislova A. \u003cem\u003eet al\u003c/em\u003e. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010;\u003cstrong\u003e376\u003c/strong\u003e:687\u0026ndash;97.\u003c/li\u003e\n\u003cli\u003eCunningham D, Starling N, Rao S. \u003cem\u003eet al\u003c/em\u003e. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 2008;\u003cstrong\u003e358\u003c/strong\u003e:36\u0026ndash;46.\u003c/li\u003e\n\u003cli\u003eYamaguchi K, Sawaki A, Doi T. \u003cem\u003eet al\u003c/em\u003e. Efficacy and safety of capecitabine plus cisplatin in Japanese patients with advanced or metastatic gastric cancer: subset analyses of the AVAGAST study and the ToGA study. Gastric Cancer 2013;\u003cstrong\u003e16\u003c/strong\u003e:175\u0026ndash;82.\u003c/li\u003e\n\u003cli\u003eYokokawa T, Kawakami K, Mae Y. \u003cem\u003eet al\u003c/em\u003e. Risk factors exacerbating hand-foot skin reaction induced by capecitabine plus oxaliplatin with or without bevacizumab therapy. Ann Pharmacother 2015;49:1120\u0026ndash;4.\u003c/li\u003e\n\u003cli\u003eLeicher LW, de Graaf JC, Coers W. \u003cem\u003eet al\u003c/em\u003e. Tolerability of capecitabine monotherapy in metastatic colorectal cancer: A real-world study. Drugs R D 2017;\u003cstrong\u003e17\u003c/strong\u003e:117\u0026ndash;24.\u003c/li\u003e\n\u003cli\u003eLakkunarajah S, Breadner DA, Zhang H. \u003cem\u003eet al\u003c/em\u003e. The influence of adjuvant chemotherapy dose intensity on five-year outcomes in resected colon cancer: A single centre retrospective analysis. Curr Oncol 2021;\u003cstrong\u003e28\u003c/strong\u003e:4031\u0026ndash;41.\u003c/li\u003e\n\u003cli\u003eScheithauer W, Blum J. Coming to grips with hand-foot syndrome. Insights from clinical trials evaluating capecitabine. Oncology (Williston Park) 2004;\u003cstrong\u003e18\u003c/strong\u003e:1161\u0026ndash;8, 1173;discussion 1173\u0026ndash;66, 1181\u0026ndash;64.\u003c/li\u003e\n\u003cli\u003eDegen A, Alter M, Schenck F. \u003cem\u003eet al\u003c/em\u003e. The hand-foot-syndrome associated with medical tumor therapy - classification and management. J Dtsch Dermatol Ges 2010;\u003cstrong\u003e8\u003c/strong\u003e:652\u0026ndash;61.\u003c/li\u003e\n\u003cli\u003eHofheinz RD, Gencer D, Schulz H. \u003cem\u003eet al\u003c/em\u003e. Mapisal versus urea cream as prophylaxis for capecitabine-associated hand-foot syndrome: A randomized phase III trial of the AIO quality of life working group. J Clin Oncol 2015;\u003cstrong\u003e33\u003c/strong\u003e:2444\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eWolf SL, Qin R, Menon SP. \u003cem\u003eet al\u003c/em\u003e. Placebo-controlled trial to determine the effectiveness of a urea/lactic acid-based topical keratolytic agent for prevention of capecitabine-induced hand-foot syndrome: North Central Cancer Treatment Group Study N05C5. J Clin Oncol 2010;\u003cstrong\u003e28\u003c/strong\u003e:5182\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eLu W, Huang Z, Chen S. \u003cem\u003eet al\u003c/em\u003e. The effectiveness of EVOSKIN\u0026reg;Palm and sole moisturizing cream in treating capecitabine-associated hand-foot syndrome: a randomized double-blind clinical trial. Ann Palliat Med 2021;\u003cstrong\u003e10\u003c/strong\u003e:3009\u0026ndash;17.\u003c/li\u003e\n\u003cli\u003eZhang RX, Wu XJ, Lu SX. \u003cem\u003eet al\u003c/em\u003e. The effect of COX-2 inhibitor on capecitabine-induced hand-foot syndrome in patients with stage II/III colorectal cancer: a phase II randomized prospective study. J Cancer Res Clin Oncol 2011;\u003cstrong\u003e137\u003c/strong\u003e:953\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eZhang RX, Wu XJ, Wan DS. \u003cem\u003eet al\u003c/em\u003e. Celecoxib can prevent capecitabine-related hand-foot syndrome in stage II and III colorectal cancer patients: result of a single-center, prospective randomized phase III trial. Ann Oncol 2012;\u003cstrong\u003e23\u003c/strong\u003e:1348\u0026ndash;53.\u003c/li\u003e\n\u003cli\u003eYamamoto D, Yamamoto C, Iwase S. \u003cem\u003eet al\u003c/em\u003e. Efficacy of vitamin E treatment for hand-foot syndrome in patients receiving capecitabine. Breast Care (Basel) 2010;\u003cstrong\u003e5\u003c/strong\u003e:415\u0026ndash;6.\u003c/li\u003e\n\u003cli\u003eJo SJ, Shin H, Jo S \u003cem\u003eet al\u003c/em\u003e. Prophylactic and therapeutic efficacy of pyridoxine supplements in the management of hand-foot syndrome during chemotherapy: a meta-analysis. Clin Exp Dermatol 2015;\u003cstrong\u003e40\u003c/strong\u003e:260\u0026ndash;70.\u003c/li\u003e\n\u003cli\u003eSon HS, Lee WY, Lee WS. \u003cem\u003eet al\u003c/em\u003e. Compliance and effective management of the hand-foot syndrome in colon cancer patients receiving capecitabine as adjuvant chemotherapy. Yonsei Med J 2009;\u003cstrong\u003e50\u003c/strong\u003e:796\u0026ndash;802.\u003c/li\u003e\n\u003cli\u003eVan Cutsem E, Twelves C, Cassidy J. \u003cem\u003eet al\u003c/em\u003e. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol 2001;\u003cstrong\u003e19\u003c/strong\u003e:4097\u0026ndash;106.\u003c/li\u003e\n\u003cli\u003eBlum JL, Jones SE, Buzdar AU. \u003cem\u003eet al\u003c/em\u003e. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 1999;\u003cstrong\u003e17\u003c/strong\u003e:485\u0026ndash;93.\u003c/li\u003e\n\u003cli\u003eLacouture ME, Sibaud V, Gerber PA. \u003cem\u003eet al\u003c/em\u003e. Prevention and management of dermatological toxicities related to anticancer agents: ESMO Clinical Practice Guidelines(☆). Ann Oncol 2021;32:157\u0026ndash;70.\u003c/li\u003e\n\u003cli\u003eDiasio RB. Oral DPD-inhibitory fluoropyrimidine drugs. Oncology (Williston Park) 2000;14:19\u0026ndash;23.\u003c/li\u003e\n\u003cli\u003eYokomichi N, Nagasawa T, Coler-Reilly A. \u003cem\u003eet al\u003c/em\u003e. Pathogenesis of hand-foot syndrome induced by PEG-modified liposomal doxorubicin. Hum Cell 2013;\u003cstrong\u003e26\u003c/strong\u003e:8\u0026ndash;18.\u003c/li\u003e\n\u003cli\u003eIimura Y, Furukawa N, Ishibashi M. \u003cem\u003eet al\u003c/em\u003e. Study protocol of a single-arm phase 2 study evaluating the preventive effect of topical hydrocortisone for capecitabine-induced hand-foot syndrome in colorectal cancer patients receiving adjuvant chemotherapy with capecitabine plus oxaliplatin (T-CRACC study). BMC Gastroenterol 2022;\u003cstrong\u003e22\u003c/strong\u003e:341.\u003c/li\u003e\n\u003cli\u003eSanthosh A, Kumar A, Pramanik R \u003cem\u003eet al\u003c/em\u003e. Randomized double-blind, placebo-controlled study of topical diclofenac in the prevention of hand-foot syndrome in patients receiving capecitabine (the D-TORCH study). Trials 2022;\u003cstrong\u003e23\u003c/strong\u003e:420.\u003c/li\u003e\n\u003cli\u003eDrake RD, Lin WM, King M. \u003cem\u003eet al\u003c/em\u003e. Oral dexamethasone attenuates Doxil-induced palmar-plantar erythrodysesthesias in patients with recurrent gynecologic malignancies. Gynecol Oncol 2004;\u003cstrong\u003e94\u003c/strong\u003e:320\u0026ndash;4.\u003c/li\u003e\n\u003cli\u003eBrown J, Burck K, Black D, Collins C. Treatment of cytarabine acral erythema with corticosteroids. J Am Acad Dermatol 1991;\u003cstrong\u003e24\u003c/strong\u003e:1023\u0026ndash;5.\u003c/li\u003e\n\u003cli\u003eHoff PM, Valero V, Ibrahim N. \u003cem\u003eet al\u003c/em\u003e. Hand-foot syndrome following prolonged infusion of high doses of vinorelbine. Cancer 1998;\u003cstrong\u003e82\u003c/strong\u003e:965\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eLin E, Morris JS, Ayers GD. Effect of celecoxib on capecitabine-induced hand-foot syndrome and antitumor activity. Oncology (Williston Park) 2002;\u003cstrong\u003e16\u003c/strong\u003e:31\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eSanthosh A, Sharma A, Bakhshi S. \u003cem\u003eet al\u003c/em\u003e. Topical diclofenac for prevention of capecitabine-associated hand-foot syndrome: A double-blind randomized controlled trial. J Clin Oncol 2024;42:1821\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eOstwal V, Kapoor A, Mandavkar S \u003cem\u003eet al\u003c/em\u003e. Effect of a structured teaching module including intensive prophylactic measures on reducing the incidence of capecitabine-induced hand-foot syndrome: Results of a prospective randomized phase III study. Oncologist 2020;\u003cstrong\u003e25\u003c/strong\u003e:e1886\u0026ndash;92.\u003c/li\u003e\n\u003cli\u003eDanno K, Hata T, Tamai K. \u003cem\u003eet al\u003c/em\u003e. Interim analysis of a phase II trial evaluating the safety and efficacy of capecitabine plus oxaliplatin (XELOX) as adjuvant therapy in Japanese patients with operated stage III colon cancer. Cancer Chemother Pharmacol 2017;\u003cstrong\u003e80\u003c/strong\u003e:777\u0026ndash;85.\u003c/li\u003e\n\u003cli\u003eTwelves C, Wong A, Nowacki MP. \u003cem\u003eet al\u003c/em\u003e. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 2005;\u003cstrong\u003e352\u003c/strong\u003e:2696\u0026ndash;704.\u003c/li\u003e\n\u003cli\u003eCassidy J, Clarke S, D\u0026iacute;az-Rubio E \u003cem\u003eet al\u003c/em\u003e. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 2008;\u003cstrong\u003e26\u003c/strong\u003e:2006\u0026ndash;12.\u003c/li\u003e\n\u003cli\u003eJiang Y, Mason M, Cho Y. \u003cem\u003eet al\u003c/em\u003e. Tolerance to oral anticancer agent treatment in older adults with cancer: a secondary analysis of data from electronic health records and a pilot study of patient-reported outcomes. BMC Cancer 2022;\u003cstrong\u003e22\u003c/strong\u003e:950.\u003c/li\u003e\n\u003cli\u003eIlich AI, Danilak M, Kim CA. \u003cem\u003eet al\u003c/em\u003e. Effects of gender on capecitabine toxicity in colorectal cancer. J Oncol Pharm Pract 2016;\u003cstrong\u003e22\u003c/strong\u003e:454\u0026ndash;60.\u003c/li\u003e\n\u003cli\u003e\u0026Ouml;zdemir BC, Gerard CL, Espinosa da Silva C. Sex and gender differences in anticancer treatment toxicity: A call for revisiting drug dosing in oncology. Endocrinology 2022;\u003cstrong\u003e163\u003c/strong\u003e.\u003c/li\u003e\n\u003cli\u003eWagner AD. Sex differences in cancer chemotherapy effects, and why we need to reconsider BSA-based dosing of chemotherapy. ESMO Open 2020;5:e000770.\u003c/li\u003e\n\u003cli\u003eKang YK, Lee SS, Yoon DH. \u003cem\u003eet al\u003c/em\u003e. Pyridoxine is not effective to prevent hand-foot syndrome associated with capecitabine therapy: results of a randomized, double-blind, placebo-controlled study. J Clin Oncol 2010;\u003cstrong\u003e28\u003c/strong\u003e:3824\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eOta M, Tatsumi K, Suwa H. \u003cem\u003eet al\u003c/em\u003e. The effect of pyridoxine for prevention of hand-foot syndrome in colorectal cancer patients with adjuvant chemotherapy using capecitabine: A randomized study. Hepatogastroenterology 2014;\u003cstrong\u003e61\u003c/strong\u003e:1008\u0026ndash;13.\u003c/li\u003e\n\u003cli\u003eYap YS, Kwok LL, Syn N \u003cem\u003eet al\u003c/em\u003e. Predictors of hand-foot syndrome and pyridoxine for prevention of capecitabine-induced hand-foot syndrome: A randomized clinical trial. JAMA Oncol 2017;\u003cstrong\u003e3\u003c/strong\u003e:1538\u0026ndash;45.\u003c/li\u003e\n\u003cli\u003eToyama T, Yoshimura A, Hayashi T. \u003cem\u003eet al\u003c/em\u003e. A randomized phase II study evaluating pyridoxine for the prevention of hand-foot syndrome associated with capecitabine therapy for advanced or metastatic breast cancer. Breast Cancer 2018;\u003cstrong\u003e25\u003c/strong\u003e:729\u0026ndash;35.\u003c/li\u003e\n\u003cli\u003eWatanabe K, Ishibe A, Watanabe J. \u003cem\u003eet al\u003c/em\u003e. The effect of TJ-28 (Eppikajutsuto) on the prevention of hand-foot syndrome using capecitabine for colorectal cancer: The Yokohama Clinical Oncology Group Study (YCOG1102). Indian J Gastroenterol 2020;\u003cstrong\u003e39\u003c/strong\u003e:204\u0026ndash;10.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table 3","content":"\u003cp\u003eTable 3 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Capecitabine-induced hand-foot syndrome, topical diclofenac cream, protocol","lastPublishedDoi":"10.21203/rs.3.rs-6299256/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6299256/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003e Clinical evidence on preventive therapy for capecitabine-induced hand-foot syndrome (HFS) is limited, and moisturizing and avoiding local pressure are recommended in guidelines. Although the precise pathogenesis and mechanisms of HFS remain unclear, inflammatory reactions are thought to be involved. The preventive effects of topical diclofenac gel have been reported from India. However, the trial did not evaluate its preventive effect for the sole, and the HFS incidence in the control group was lower than that in previous reports. Therefore, this study aims to confirm the preventive effects of diclofenac sodium 0.1% cream for capecitabine-induced HFS.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis is a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. Patients scheduled to receive capecitabine-containing chemotherapy are enrolled, and participants are prophylactically treated with topical diclofenac sodium 0.1% cream or placebo alongside standard preventive therapy. The primary endpoint is an incidence of grade 2 HFS within 3 months. The secondary endpoints include time to onset of HFS, incidences of dose reduction, schedule delay, discontinuation caused by capecitabine-induced HFS, dose intensity of capecitabine, an incidence of grade\u0026thinsp;\u0026ge;\u0026thinsp;2 peripheral sensory neuropathy, incidences of other capecitabine-related adverse events (nausea, vomiting, appetite loss, diarrhea, oral mucositis, pigmentation, abnormality of liver and renal functions, and neutropenia).\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e \u003cp\u003eIf this study meets the primary endpoint, a new standard preventive therapy for HFS will be established. Moreover, the use of topical diclofenac cream alongside high-dose capecitabine may enhance chemotherapy efficacy.\u003c/p\u003e","manuscriptTitle":"A randomized, double-blind, placebo-controlled phase III study evaluating the preventive effect of diclofenac cream on capecitabine-related hand-foot syndrome: Study protocol of J-SUPPORT2401/JORTC-SUP06 (J-DIRECT)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-21 10:06:15","doi":"10.21203/rs.3.rs-6299256/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revisions","date":"2025-04-21T01:09:45+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-03-30T10:12:41+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-30T10:04:28+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-27T02:36:25+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Clinical Oncology","date":"2025-03-24T22:26:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"a5babcb2-26e5-4fea-a96a-edc778e1d013","owner":[],"postedDate":"April 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-05-19T16:05:50+00:00","versionOfRecord":{"articleIdentity":"rs-6299256","link":"https://doi.org/10.1007/s10147-025-02789-z","journal":{"identity":"international-journal-of-clinical-oncology","isVorOnly":false,"title":"International Journal of Clinical Oncology"},"publishedOn":"2025-05-14 15:57:18","publishedOnDateReadable":"May 14th, 2025"},"versionCreatedAt":"2025-04-21 10:06:15","video":"","vorDoi":"10.1007/s10147-025-02789-z","vorDoiUrl":"https://doi.org/10.1007/s10147-025-02789-z","workflowStages":[]},"version":"v1","identity":"rs-6299256","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6299256","identity":"rs-6299256","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}