Biweekly CAPOX versus Triweekly CAPOX in the adjuvant therapy of post-surgery CRC: a randomized controlled trial

Biweekly CAPOX versus Triweekly CAPOX in the adjuvant therapy of post-surgery CRC: a randomized controlled trial | 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 Biweekly CAPOX versus Triweekly CAPOX in the adjuvant therapy of post-surgery CRC: a randomized controlled trial Hangyu Zhang, Danyang Wang, Zhou Tong, Tao Xiang, Xiaomeng Dai, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2823745/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Adjuvant CAPOX (capecitabine plus oxaliplatin) provided significant disease-free survival (DFS) benefit in patients with high-risk stage II or stage III colorectal cancer (CRC). Conventional triweekly CAPOX results in 14-38% 3-4 grade hematological toxicity. Modified biweekly CAPOX was observed to be generally well-tolerated in previous studies. Methods: High-risk stage II and stage III post-surgery CRC patients were randomized in the control triweekly group (intravenous infusion of oxaliplatin 130 mg/m2 on day 1 and oral capecitabine 1000 mg/m2, twice daily from d1 to d14) and the experimental biweekly group (intravenous infusion of oxaliplatin 85 mg/m2 on day 1 and oral capecitabine 1000 mg/m2, twice daily from d1 to d10). The primary endpoint was incidence of thrombocytopenia. The secondary endpoint was 18-month DFS rate. Results: Between Jul 25, 2018, and May 14, 2021, 160 patients were 1:1 randomly enrolled and received treatment. The primary endpoint thrombocytopenia occurred 33% and 49% in biweekly and triweekly group ( P =0.02). The second endpoint 18-month DFS in 3-month group was 94.1% in biweekly CAPOX group, and 93.8% in triweekly CPOX group ( P =0.96). Neutropenia was 36% and 51% in biweekly and triweekly group, respectively ( P =0.04). The rate of uncomplete therapy patient was 7% and 15% in biweekly and triweekly group, respectively ( P =0.13). Conclusion: Biweekly CAPOX presented significant less thrombocytopenia and neutropenia than triweekly CAPOX regimen. And biweekly CAPOX did not affect the 18-month DFS rate. Clinical trial registration: First registration date: 21/06/2018. ClinicalTials.gov (NCT03564912). Adjuvant chemotherapy Modified regimen Thrombocytopenia Neutropenia Adverse event Figures Figure 1 Figure 2 Figure 3 Introduction Colorectal cancer (CRC) was estimated to be the fourth most common cancer and the second leading cause of cancer deaths worldwide( 1 ). A large proportion of CRC patients are diagnosed in advanced stage cause no warning symptoms( 2 ). Surgery remains the foundation of curative treatment, and perioperative chemotherapy, especially postoperative adjuvant chemotherapy plays particularly important role. To improve overall and disease-free survival, adjuvant chemotherapy is widely applied in high-risk stage II and stage III CRC patients. Since the MOSAIC study( 3 ), CAPOX (capecitabine and oxaliplatin) and FOLFOX (fluorouracil plus leucovorin and oxaliplatin) had become the standard adjuvant regimens for high-risk stage II and stage III CRC( 4 ). However, whether adjuvant chemotherapy improves clinical outcomes of patients with stage II or curatively resected stage IV colon cancer, and whether duration lasts for 3 months or 6 months, are still controversial. Recently years, a few studies( 5 , 6 ) have focused on the duration course, hoping to reduce treatment-related adverse events while providing intact clinical benefits. Peripheral sensory neuropathy (PSN) is the most criticized adverse event in these studies and its incidence was significantly lower with 3-month therapy than with 6-month therapy( 7 , 8 ). Indeed, hematologic toxicity, especially thrombocytopenia, is an equally important factor affecting the integrity of adjuvant treatment. It is reported that grade ≥ 3 thrombocytopenia was about 5% in CAPOX adjuvant treated patients( 9 ), compared with 0-1.7% in FOLFOX adjuvant treated patients( 3 , 5 ). Previous studies have not paid sufficient attention to the difference between the two treatment regimens and the proportion of thrombocytopenia leading to treatment intolerance. Indeed, biweekly CAPOX was reported to have no incidence of grade 3 thrombocytopenia in first-line treatment of metastases CRC in several studies( 10 , 11 ). This may be related to a modified single dose of oxaliplatin, which has not been validated in adjuvant therapy. Therefore, we conducted this pilot study of biweekly CAPOX versus triweekly CAPOX for high-risk stage II and stage III colon cancer to assess the potential implications in modified single dose oxaliplatin for Asian patients. One of the key objectives of our study was to provide data to confirm the treatment related adverse events difference between the two regimens and its impact on treatment tolerability. Another objective was to explore whether modified biweekly CAPOX could affect disease free survival (DFS) in adjuvant CRC patients. Materials and Methods Study design This study is an open-label, randomized, single-center pilot study conducted in China. Patients who had complete resection for high-risk stage II and stage III colon cancer were randomized 1:1 assigned to receive either biweekly CAPOX or triweekly CAPOX. The duration time of chemotherapy refer to the recently published adjuvant studies( 12 ) (high-risk stage II and low-risk stage III population received 3-month CAPOX therapy, high-risk stage III population received 6-month CAPOX therapy). The inclusion criteria of patients were curatively resection of high-risk stage II and stage III colon cancer patients, the age range from 18–75 years, ECOG performance status 0–2, adequate renal, hepatic and bone marrow function. The major exclusion criteria were those who received neoadjuvant treatment before surgery or unstable heart disease, active inflammation, etc. The Ethics Committee of the First Affiliated Hospital of Zhejiang University School of Medicine approved the protocol. This study is registered at the Clinical Trials (NCT 03564912). The primary endpoint was incidence of thrombocytopenia. The secondary endpoint was 18-month DFS rate defined as the proportion of patients who relapse or death from any case patients within 18 months. Treatment Patients were 1:1 randomized to the biweekly group or triweekly group via blocked randomization with random block size of 4 to balance enrolled participants. Triweekly CAPOX include intravenous infusion of oxaliplatin 130 mg/m2 on day 1 and oral capecitabine 1000 mg/m2, twice daily from d1 to d14, biweekly CAPOX include intravenous infusion of oxaliplatin 85 mg/m2 on day 1 and oral capecitabine 1000 mg/m2, twice daily from d1 to d10. Patients were evaluated for disease recurrence by abdominal computed tomography (CT) scans and serum CEA every 3 months, chest CT scans every 6 months, and colonoscopy every 12 months. The Common Terminology Criteria for Adverse Events Version (CTCAE) 5.0 was used to evaluate AEs every single cycle of treatment till one month later after final treatment. Therapeutic dose was planned to reduce by 20% when grade ≥ 3 adverse events happened. Sample size Sample size calculation was performed with thrombocytopenia as the primary outcome, use a significant level of 5% and a power level of 80%. 80 participants were required for each group based on 0.44 effect size. Statistical analysis DFS curve was derived by Kaplan-Meier estimation. Cox proportional hazard model was used to calculate the HRs and 95% CIs between biweekly group and triweekly group. The AE frequency was compared using chi-square test. For all tests, P < 0.05 was defined as statistically significant. The IBM SPSS Statistics (Version 26; IBM Corp., New York, USA) was used for the analyses. The GraphPad Prism 8 (GraphPad Software, Inc., La Jolla, CA, USA) was used for chart making. Results Patients Between 25 July 2018 and 14 May 2021, 160 patients were enrolled in our study 1:1 randomized received biweekly CAPOX or triweekly CAPOX adjuvant chemotherapy as shown in CONSORT diagram (Fig. 1 ). All enrolled patients received at least one cycle therapy and were included in final analysis. The last follow-up time was 25 December 2022, and the median follow-up period was 27 months. The baseline characteristics were shown in Table 1 . There were 80 patients in biweekly group and another 80 patients in triweekly group, with balanced characteristics between two groups. Sixty- three percent of patients (100/160) were high-risk stage II and low-risk stage III patients and received 3-month treatment, and thirty-seven percent of patients were high-risk stage III patients and received 6-month treatment. There were 47 patients had right-side primary tumor and 103 patients had left-side primary tumor. The proportion of elevated serum CEA and CA19-9 before surgery were 30% and 19%. Table 1 Characteristics of all enrolled patients Biweekly CAPOX (n = 80) Triweekly CAPOX (n = 80) P value Duration of treatment 0.74 6-month 31 (38) 29 (36) 3-month 49 (62) 51 (64) Age, median(range), years 58 (32–77) 57 (24–78) 0.48 <70 68 (85) 71 (88) ≥70 12 (15) 9 (12) Sex 0.19 Male 45 (56) 53 (66) Female 35 (46) 27 (34) Location of primary tumor 0.19 Right 25 (31) 22 (27) Left 52 (65) 51 (64) NA 3 (4) 7 (9) T stage 0.16 T1-3 68 (85) 61 (76) T4 12 (15) 19 (24) N statge 0.55 N0 16 (20) 17 (21) N1 40 (50) 45 (56) N2 24 (30) 18 (23) Number of haversted lymph nodes 0.32 <12 2 (2) 0 (0) ≥12 70 (88) 72 (90) NA 8 (10) 8 (10) CEA before surgery 0.79 <5 45 (56) 47 (59) ≥5 26 (32) 22 (57) NA 9 (12) 11 (88) CA199 before surgery 0.83 <37 56 (70) 54 (68) ≥37 15 (19) 15 (19) NA 9 (11) 11 (13) Recurrence patient 13 (16) 9 (11) 0.35 Uncomplete therapy patient 6 (7) 12 (15) 0.13 Thrombocytopenia and other adverse events All grade thrombocytopenia occurred 33% in biweekly group and 49% in triweekly group ( P = 0.02). In the biweekly group, 3-month treatment subgroup presented 28% thrombocytopenia and 6-month treatment subgroup was 38%. In the triweekly group, 3-month treatment group presented 43% thrombocytopenia and 6-month treatment subgroup was 58%. However, grade ≥ 3 thrombocytopenia was 5% versus. 9% in biweekly and triweekly group with no significant difference ( P = 0.35). The total adverse events are shown in Table 2 . Overall patients randomly assigned to triweekly CAPOX treatment had significantly more adverse events than patients receiving biweekly CAPOX treatment, especially all grade neutropenia ( P = 0.04). No significant differences were observed in more than grade 3 neutropenia ( P = 0.17). In the biweekly group, 6 patients (7.5%) failed to complete adjuvant chemotherapy due to treatment intolerance. In the triweekly group, the discontinue patients was 12 (15%), including 11 patients with treatment intolerance and 1 patient found to have leukemia during the treatment. In patients receiving 6-month CAPOX, 21% (13/60) of the patients experienced grade ≥ 2 PSN, whereas 10% (10/100) of the patients in the 3-month CAPOX group experienced grade ≥ 2 PSN. There was no treatment related death. Table 2 Adverse events by regimen and treatment duration in all patients Adverse events Biweekly CAPOX group (n = 80) Triweekly CAPOX group (n = 80) P value 3-month treatment (N = 49) 6-month treatment (N = 31) total 3-month treatment (N = 51) 6-month treatment (N = 29) total Hematological Neutropenia 19(38) 10(32) 29(36) 24(47) 17(58) 41(51) 0.040 Neutropenia(≥ 3) 1(2) 0 1(1) 2(4) 2(7) 4(5) 0.173 Thrombocytopenia 14(28) 12(38) 26(33) 22(43) 17(58) 39(49) 0.027 Thrombocytopenia(≥ 3) 1(2) 3(10) 4(5) 5(10) 2(7) 7(9) 0.349 Anemia 10(20) 8(25) 18(22) 7(14) 13(45) 20(25) 0.710 Non-hematological PNS 24(49) 16(52) 40(50) 32(62) 15(52) 47(58) 0.267 PNS(≥ 2) 5(10) 6(19) 11(14) 7(14) 4(14) 11(14) 1.0 Liver disfunction 15(30) 7(22) 22(27) 22(43) 10(34) 32(40) 0.095 Hyperbilirubinemia 5(10) 6(19) 11(14) 5(10) 7(24) 12(15) 0.822 Diarrhea (≥ 3) 0 1(3) 1(1) 0 1(3) 1(1) 1.0 Vomiting (≥ 3) 0 0 0 2(4) 0 2(2) 0.155 Disease-free survival At the time of analysis, 21 events had been reported (13 in the biweekly group and 9 in the triweekly group). The Kaplan-Meier plots for DFS among 3-month and 6-month groups are shown in Fig. 2 – 3 . The 18-month DFS rate was 94.1% in 3-month biweekly CAPOX group, and 93.8% in the 3-month triweekly CPOX group ( P = 0.96). The 18-month DFS rate was 89.6% in the 6-month biweekly CAPOX group, and 93.5% in the 6-month triweekly CAPOX group ( P = 0.61). The median disease-free survival time of 13 relapse patients is 13.3 months (range 1.7–52.5 months). There were two patients died due to disease progression in triweekly group. Discussion Our study is the first study explore the safety and efficacy of biweekly CAPOX and triweekly CAPOX in colorectal adjuvant treatment. Previous study had shown that biweekly CAPOX had modest efficacy and an acceptable safety profile in the treatment of advanced gastric cancer( 13 ). In our study, we enrolled high-risk stage II and stage III post-surgery colorectal cancer patients to certify its advantage of biweekly CAPOX in adjuvant area. CAPOX is reported to have significant higher grade 3–4 thrombocytopenia than FOLFOX (3–12% vs. 1–6%)( 14 ). However, the negative effect of thrombocytopenia induced by CAPOX has not been paid enough attention. Indeed, not only grade 3–4 thrombocytopenia affects treatment, but grade 2 thrombocytopenia also requires drug intervention and may lead to delayed treatment( 15 ). Our study finds that all grade thrombocytopenia significant reduced by modified biweekly CAPOX, which has not been explored before. The incidence of all hematological AEs was lower in the biweekly group than in the triweekly group, concomitant lower treatment discontinuation. In the biweekly CAPOX group, 74 patients (92.5%) completed all courses of adjuvant chemotherapy, which is higher than triweekly group and previous adjuvant study( 16 ). The completion rate of treatment is considered to be related to OS benefits( 16 ). The high completion rate of our study due to the high proportion of patients who underwent three-month treatment and the reduction of AEs of the modified biweekly CAPOX regimen. And it is shown that grade ≥ 2 PSN was more common in 6-month treatment patients, which was consistent with the finding of previous studies( 17 , 18 ). It is reported that the median DFS in relapsed patients aged less than 50 years was 13 months( 19 ). And in another retrospective study, the median recurrence free survival was 1.3 years( 20 ). Thus, we set 18-month DFS as second endpoint. In our study, the median DFS was 13.3 months in relapse patients. The DFS curves of biweekly and triweekly groups were similar, and the 18-month DFS rate did not reach significant difference between the two groups. However, the overall number of patients was too low to establish whether biweekly CAPOX is inferior to triweekly CAPOX. There may have new revolution of adjuvant chemotherapy of CRC in the future. More and more studies support the use of ctDNA test to identify patients who are at increased risk of recurrence and are potential benefit from treatment( 21 , 22 ). And it is reported that tumor deposits (TD) positive patients proven to have significantly worse outcomes, especially in N1a-b patients( 23 ). The role of TD deserves further scrutiny. And the best adjuvant treatment option of MSI-H CRC is still inconclusive. Although post-surgery CRC patients should be segmented in different groups, adjuvant treatment is still on the base of fluorouracil and oxaliplatin. We believe that modified biweekly CAPOX can reduce treatment-related AEs and turn out to be a better tolerance regimen for most CRC patients. However, this is a pilot study with finite patients’ number, and did not have the statistical power to confirm the non-inferior of biweekly CAPOX to triweekly CAPOX. Further study still needed to confirm the advantages of biweekly CAPOX. Conclusion Our data suggests that biweekly CAPOX could be an acceptable alternative treatment option with favorable risk-benefit for CRC adjuvant chemotherapy. A modified biweekly CAPOX reduced hematological AEs and improved treatment tolerance, and it did not compromise the DFS. Declarations Ethics approval and consent to participate. This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of The First Affiliated hospital of Zhejiang University. Informed consent was obtained from all individual participants included in the study. Consent for publication Not applicable. Availability of data and materials The datasets generated during and analyzed during the current study are available in link: https://pan.baidu.com/s/19-86yE2hxXxXUGIjGSHzww code:gtn3 Competing interests The authors have no relevant financial or non-financial interests to disclose. Funding This work was supported by Natural Science Foundation of Zhejiang Province [grant number LQ23H160041]. Authors’ contribution All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Hangyu Zhang, Danyang Wang, Zhou Tong, Tao Xiang, Xiaomeng Dai, Xuanwen Bao and Xudong Zhu. The first draft of the manuscript was written by Hangyu Zhang, Wenbin Chen, review and editing by Lulu Liu, Yi Zheng, Peng Zhao and Weijia Fang, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Acknowledgements This study would like to appreciate Ms. Shiting Wen for her support and every participant enrolled in this study. References Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. 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Universtiy","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Weijia","middleName":"","lastName":"Fang","suffix":""},{"id":211467764,"identity":"22bf5d40-d59f-4b31-bbe2-acd65ca42d3d","order_by":11,"name":"Wenbin Chen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5ElEQVRIiWNgGAWjYHACNoYEBhBiPsAgAeIfIF4LWwIJWhjAWngMIHxCWgyO9x578HCHXR6/dM/nD5ZtDHJ8NxIYPxfg03LmXLpB4pnkYsk5ZzcYSLYxGEveSGCWnoFHi9mNHDOJxLYDiRtu5G5IAGoBMhLYmHnwabn/BqJl/42cBweAWuoJa7nBA7VFIoexAaglwYCQFvszOeYGiW3JiTNupBkzSJyTMJx55mGzND4tku1nzB7+bLNL7J+R/PizRJmNPN/x5IOf8WlBAcwS4MhkbCBWA1DtB+LVjoJRMApGwQgCAPCnTrZ55nx9AAAAAElFTkSuQmCC","orcid":"","institution":"First Affiliated Hospital of Zhejiang Universtiy","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Wenbin","middleName":"","lastName":"Chen","suffix":""}],"badges":[],"createdAt":"2023-04-16 14:44:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2823745/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2823745/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":39123536,"identity":"7c0b16e7-78e7-481b-b9d9-a255a4e59b37","added_by":"auto","created_at":"2023-06-26 21:37:50","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":282555,"visible":true,"origin":"","legend":"\u003cp\u003eCONSORT flow diagram\u003c/p\u003e","description":"","filename":"figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2823745/v1/db60fe9d1bde1dbb14944442.jpg"},{"id":39123535,"identity":"7b5debe6-5fac-449d-b195-5b7d9bef20c6","added_by":"auto","created_at":"2023-06-26 21:37:50","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":322159,"visible":true,"origin":"","legend":"\u003cp\u003eOverall disease-free survival (DFS) according to biweekly and triweekly CAPOX in 3-month treatment duration group.\u003c/p\u003e","description":"","filename":"figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2823745/v1/2a9a451b96ae16d777c8e55d.jpg"},{"id":39123537,"identity":"d9a623e4-505a-4a75-8af1-8297c9685a9e","added_by":"auto","created_at":"2023-06-26 21:37:50","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":334711,"visible":true,"origin":"","legend":"\u003cp\u003eOverall disease-free survival (DFS) according to biweekly and triweekly CAPOX in 6-month treatment duration group.\u003c/p\u003e","description":"","filename":"figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2823745/v1/7904e9a6f646542781516730.jpg"},{"id":39591710,"identity":"fe639474-ac4a-4da9-b39c-8e097ac63580","added_by":"auto","created_at":"2023-07-05 16:29:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":512786,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2823745/v1/68a38416-7175-4445-adcf-d60c5d6c6bba.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Biweekly CAPOX versus Triweekly CAPOX in the adjuvant therapy of post-surgery CRC: a randomized controlled trial","fulltext":[{"header":"Introduction","content":"\u003cp\u003eColorectal cancer (CRC) was estimated to be the fourth most common cancer and the second leading cause of cancer deaths worldwide(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). A large proportion of CRC patients are diagnosed in advanced stage cause no warning symptoms(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Surgery remains the foundation of curative treatment, and perioperative chemotherapy, especially postoperative adjuvant chemotherapy plays particularly important role. To improve overall and disease-free survival, adjuvant chemotherapy is widely applied in high-risk stage II and stage III CRC patients.\u003c/p\u003e \u003cp\u003eSince the MOSAIC study(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e), CAPOX (capecitabine and oxaliplatin) and FOLFOX (fluorouracil plus leucovorin and oxaliplatin) had become the standard adjuvant regimens for high-risk stage II and stage III CRC(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). However, whether adjuvant chemotherapy improves clinical outcomes of patients with stage II or curatively resected stage IV colon cancer, and whether duration lasts for 3 months or 6 months, are still controversial. Recently years, a few studies(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) have focused on the duration course, hoping to reduce treatment-related adverse events while providing intact clinical benefits. Peripheral sensory neuropathy (PSN) is the most criticized adverse event in these studies and its incidence was significantly lower with 3-month therapy than with 6-month therapy(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Indeed, hematologic toxicity, especially thrombocytopenia, is an equally important factor affecting the integrity of adjuvant treatment. It is reported that grade\u0026thinsp;\u0026ge;\u0026thinsp;3 thrombocytopenia was about 5% in CAPOX adjuvant treated patients(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e), compared with 0-1.7% in FOLFOX adjuvant treated patients(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Previous studies have not paid sufficient attention to the difference between the two treatment regimens and the proportion of thrombocytopenia leading to treatment intolerance. Indeed, biweekly CAPOX was reported to have no incidence of grade 3 thrombocytopenia in first-line treatment of metastases CRC in several studies(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). This may be related to a modified single dose of oxaliplatin, which has not been validated in adjuvant therapy.\u003c/p\u003e \u003cp\u003eTherefore, we conducted this pilot study of biweekly CAPOX versus triweekly CAPOX for high-risk stage II and stage III colon cancer to assess the potential implications in modified single dose oxaliplatin for Asian patients. One of the key objectives of our study was to provide data to confirm the treatment related adverse events difference between the two regimens and its impact on treatment tolerability. Another objective was to explore whether modified biweekly CAPOX could affect disease free survival (DFS) in adjuvant CRC patients.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThis study is an open-label, randomized, single-center pilot study conducted in China. Patients who had complete resection for high-risk stage II and stage III colon cancer were randomized 1:1 assigned to receive either biweekly CAPOX or triweekly CAPOX. The duration time of chemotherapy refer to the recently published adjuvant studies(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) (high-risk stage II and low-risk stage III population received 3-month CAPOX therapy, high-risk stage III population received 6-month CAPOX therapy). The inclusion criteria of patients were curatively resection of high-risk stage II and stage III colon cancer patients, the age range from 18\u0026ndash;75 years, ECOG performance status 0\u0026ndash;2, adequate renal, hepatic and bone marrow function. The major exclusion criteria were those who received neoadjuvant treatment before surgery or unstable heart disease, active inflammation, etc. The Ethics Committee of the First Affiliated Hospital of Zhejiang University School of Medicine approved the protocol. This study is registered at the Clinical Trials (NCT 03564912). The primary endpoint was incidence of thrombocytopenia. The secondary endpoint was 18-month DFS rate defined as the proportion of patients who relapse or death from any case patients within 18 months.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eTreatment\u003c/h2\u003e \u003cp\u003ePatients were 1:1 randomized to the biweekly group or triweekly group via blocked randomization with random block size of 4 to balance enrolled participants. Triweekly CAPOX include intravenous infusion of oxaliplatin 130 mg/m2 on day 1 and oral capecitabine 1000 mg/m2, twice daily from d1 to d14, biweekly CAPOX include intravenous infusion of oxaliplatin 85 mg/m2 on day 1 and oral capecitabine 1000 mg/m2, twice daily from d1 to d10. Patients were evaluated for disease recurrence by abdominal computed tomography (CT) scans and serum CEA every 3 months, chest CT scans every 6 months, and colonoscopy every 12 months. The Common Terminology Criteria for Adverse Events Version (CTCAE) 5.0 was used to evaluate AEs every single cycle of treatment till one month later after final treatment. Therapeutic dose was planned to reduce by 20% when grade\u0026thinsp;\u0026ge;\u0026thinsp;3 adverse events happened.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eSample size\u003c/h2\u003e \u003cp\u003eSample size calculation was performed with thrombocytopenia as the primary outcome, use a significant level of 5% and a power level of 80%. 80 participants were required for each group based on 0.44 effect size.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eDFS curve was derived by Kaplan-Meier estimation. Cox proportional hazard model was used to calculate the HRs and 95% CIs between biweekly group and triweekly group. The AE frequency was compared using chi-square test. For all tests, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was defined as statistically significant. The IBM SPSS Statistics (Version 26; IBM Corp., New York, USA) was used for the analyses. The GraphPad Prism 8 (GraphPad Software, Inc., La Jolla, CA, USA) was used for chart making.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eBetween 25 July 2018 and 14 May 2021, 160 patients were enrolled in our study 1:1 randomized received biweekly CAPOX or triweekly CAPOX adjuvant chemotherapy as shown in CONSORT diagram (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). All enrolled patients received at least one cycle therapy and were included in final analysis. The last follow-up time was 25 December 2022, and the median follow-up period was 27 months.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe baseline characteristics were shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. There were 80 patients in biweekly group and another 80 patients in triweekly group, with balanced characteristics between two groups. Sixty- three percent of patients (100/160) were high-risk stage II and low-risk stage III patients and received 3-month treatment, and thirty-seven percent of patients were high-risk stage III patients and received 6-month treatment. There were 47 patients had right-side primary tumor and 103 patients had left-side primary tumor. The proportion of elevated serum CEA and CA19-9 before surgery were 30% and 19%.\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\u003eCharacteristics of all enrolled patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBiweekly CAPOX\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;80)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTriweekly CAPOX\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;80)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of treatment\u003c/p\u003e \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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.74\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6-month\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 (38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29 (36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3-month\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49 (62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e51 (64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, median(range), years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58 (32\u0026ndash;77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57 (24\u0026ndash;78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.48\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68 (85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e71 (88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45 (56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53 (66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocation of primary tumor\u003c/p\u003e \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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25 (31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeft\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52 (65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e51 (64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT stage\u003c/p\u003e \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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT1-3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68 (85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61 (76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN statge\u003c/p\u003e \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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45 (56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of haversted lymph nodes\u003c/p\u003e \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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e70 (88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e72 (90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCEA before surgery\u003c/p\u003e \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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.79\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45 (56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47 (59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCA199 before surgery\u003c/p\u003e \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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.83\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e56 (70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54 (68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRecurrence patient\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUncomplete therapy patient\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eThrombocytopenia and other adverse events\u003c/h2\u003e \u003cp\u003eAll grade thrombocytopenia occurred 33% in biweekly group and 49% in triweekly group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02). In the biweekly group, 3-month treatment subgroup presented 28% thrombocytopenia and 6-month treatment subgroup was 38%. In the triweekly group, 3-month treatment group presented 43% thrombocytopenia and 6-month treatment subgroup was 58%. However, grade\u0026thinsp;\u0026ge;\u0026thinsp;3 thrombocytopenia was 5% versus. 9% in biweekly and triweekly group with no significant difference (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.35).\u003c/p\u003e \u003cp\u003eThe total adverse events are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Overall patients randomly assigned to triweekly CAPOX treatment had significantly more adverse events than patients receiving biweekly CAPOX treatment, especially all grade neutropenia (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.04). No significant differences were observed in more than grade 3 neutropenia (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.17). In the biweekly group, 6 patients (7.5%) failed to complete adjuvant chemotherapy due to treatment intolerance. In the triweekly group, the discontinue patients was 12 (15%), including 11 patients with treatment intolerance and 1 patient found to have leukemia during the treatment. In patients receiving 6-month CAPOX, 21% (13/60) of the patients experienced grade\u0026thinsp;\u0026ge;\u0026thinsp;2 PSN, whereas 10% (10/100) of the patients in the 3-month CAPOX group experienced grade\u0026thinsp;\u0026ge;\u0026thinsp;2 PSN. There was no treatment related death.\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\u003eAdverse events by regimen and treatment duration in all patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAdverse events\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eBiweekly CAPOX group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;80)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eTriweekly CAPOX group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;80)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3-month treatment\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;49)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6-month treatment\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;31)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003etotal\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3-month treatment\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;51)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6-month treatment\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;29)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003etotal\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHematological\u003c/p\u003e \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\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19(38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10(32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29(36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e24(47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e17(58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e41(51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.040\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutropenia(\u0026ge;\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1(1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2(4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2(7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4(5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.173\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14(28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12(38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26(33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e22(43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e17(58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e39(49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.027\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombocytopenia(\u0026ge;\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3(10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4(5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5(10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2(7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7(9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.349\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10(20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8(25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18(22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7(14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13(45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e20(25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.710\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-hematological\u003c/p\u003e \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\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePNS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24(49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16(52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40(50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e32(62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15(52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e47(58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.267\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePNS(\u0026ge;\u0026thinsp;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5(10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6(19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11(14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7(14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4(14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e11(14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver disfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15(30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7(22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22(27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e22(43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10(34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e32(40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.095\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyperbilirubinemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5(10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6(19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11(14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5(10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7(24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e12(15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.822\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiarrhea (\u0026ge;\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1(1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1(3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1(1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVomiting (\u0026ge;\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2(4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2(2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.155\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=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003eDisease-free survival\u003c/h2\u003e \u003cp\u003eAt the time of analysis, 21 events had been reported (13 in the biweekly group and 9 in the triweekly group). The Kaplan-Meier plots for DFS among 3-month and 6-month groups are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. The 18-month DFS rate was 94.1% in 3-month biweekly CAPOX group, and 93.8% in the 3-month triweekly CPOX group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.96). The 18-month DFS rate was 89.6% in the 6-month biweekly CAPOX group, and 93.5% in the 6-month triweekly CAPOX group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.61). The median disease-free survival time of 13 relapse patients is 13.3 months (range 1.7\u0026ndash;52.5 months). There were two patients died due to disease progression in triweekly group.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study is the first study explore the safety and efficacy of biweekly CAPOX and triweekly CAPOX in colorectal adjuvant treatment. Previous study had shown that biweekly CAPOX had modest efficacy and an acceptable safety profile in the treatment of advanced gastric cancer(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). In our study, we enrolled high-risk stage II and stage III post-surgery colorectal cancer patients to certify its advantage of biweekly CAPOX in adjuvant area.\u003c/p\u003e \u003cp\u003eCAPOX is reported to have significant higher grade 3\u0026ndash;4 thrombocytopenia than FOLFOX (3\u0026ndash;12% vs. 1\u0026ndash;6%)(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). However, the negative effect of thrombocytopenia induced by CAPOX has not been paid enough attention. Indeed, not only grade 3\u0026ndash;4 thrombocytopenia affects treatment, but grade 2 thrombocytopenia also requires drug intervention and may lead to delayed treatment(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Our study finds that all grade thrombocytopenia significant reduced by modified biweekly CAPOX, which has not been explored before. The incidence of all hematological AEs was lower in the biweekly group than in the triweekly group, concomitant lower treatment discontinuation. In the biweekly CAPOX group, 74 patients (92.5%) completed all courses of adjuvant chemotherapy, which is higher than triweekly group and previous adjuvant study(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). The completion rate of treatment is considered to be related to OS benefits(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). The high completion rate of our study due to the high proportion of patients who underwent three-month treatment and the reduction of AEs of the modified biweekly CAPOX regimen. And it is shown that grade\u0026thinsp;\u0026ge;\u0026thinsp;2 PSN was more common in 6-month treatment patients, which was consistent with the finding of previous studies(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIt is reported that the median DFS in relapsed patients aged less than 50 years was 13 months(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). And in another retrospective study, the median recurrence free survival was 1.3 years(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Thus, we set 18-month DFS as second endpoint. In our study, the median DFS was 13.3 months in relapse patients. The DFS curves of biweekly and triweekly groups were similar, and the 18-month DFS rate did not reach significant difference between the two groups. However, the overall number of patients was too low to establish whether biweekly CAPOX is inferior to triweekly CAPOX.\u003c/p\u003e \u003cp\u003eThere may have new revolution of adjuvant chemotherapy of CRC in the future. More and more studies support the use of ctDNA test to identify patients who are at increased risk of recurrence and are potential benefit from treatment(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). And it is reported that tumor deposits (TD) positive patients proven to have significantly worse outcomes, especially in N1a-b patients(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). The role of TD deserves further scrutiny. And the best adjuvant treatment option of MSI-H CRC is still inconclusive. Although post-surgery CRC patients should be segmented in different groups, adjuvant treatment is still on the base of fluorouracil and oxaliplatin. We believe that modified biweekly CAPOX can reduce treatment-related AEs and turn out to be a better tolerance regimen for most CRC patients.\u003c/p\u003e \u003cp\u003eHowever, this is a pilot study with finite patients\u0026rsquo; number, and did not have the statistical power to confirm the non-inferior of biweekly CAPOX to triweekly CAPOX. Further study still needed to confirm the advantages of biweekly CAPOX.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur data suggests that biweekly CAPOX could be an acceptable alternative treatment option with favorable risk-benefit for CRC adjuvant chemotherapy. A modified biweekly CAPOX reduced hematological AEs and improved treatment tolerance, and it did not compromise the DFS.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of\u0026nbsp;The First Affiliated hospital of Zhejiang University. Informed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and analyzed during the current study are available in link: https://pan.baidu.com/s/19-86yE2hxXxXUGIjGSHzww \u0026nbsp;code:gtn3\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by Natural Science Foundation of Zhejiang Province [grant number LQ23H160041].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Hangyu Zhang, Danyang Wang, Zhou Tong, Tao Xiang, Xiaomeng Dai, Xuanwen Bao and Xudong Zhu. The first draft of the manuscript was written by Hangyu Zhang, Wenbin Chen, review and editing by Lulu Liu, Yi Zheng, Peng Zhao and Weijia Fang, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study would like to appreciate Ms. Shiting Wen for her support and every participant enrolled in this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424. doi:10.3322/caac.21492\u003c/li\u003e\n\u003cli\u003eBenitez-Majano S, Fowler H, Maringe C, Di Girolamo C, Rachet B. Deriving stage at diagnosis from multiple population-based sources: colorectal and lung cancer in England. Br J Cancer. 2016;115(3):391-400. doi:10.1038/bjc.2016.177\u003c/li\u003e\n\u003cli\u003eAndre T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350(23):2343-51. doi:10.1056/NEJMoa032709\u003c/li\u003e\n\u003cli\u003eSchmoll HJ, Tabernero J, Maroun J, et al. Capecitabine Plus Oxaliplatin Compared With Fluorouracil/Folinic Acid As Adjuvant Therapy for Stage III Colon Cancer: Final Results of the NO16968 Randomized Controlled Phase III Trial. J Clin Oncol. 2015;33(32):3733-40. doi:10.1200/JCO.2015.60.9107\u003c/li\u003e\n\u003cli\u003eYamazaki 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(1):77-84. doi:10.1016/j.annonc.2020.10.480\u003c/li\u003e\n\u003cli\u003eSouglakos J, Boukovinas I, Kakolyris S, et al. Three- versus six-month adjuvant FOLFOX or CAPOX for high-risk stage II and stage III colon cancer patients: the efficacy results of Hellenic Oncology Research Group (HORG) participation to the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) project. Ann Oncol. 2019;30(8):1304-10. doi:10.1093/annonc/mdz193\u003c/li\u003e\n\u003cli\u003eIveson TJ, Sobrero AF, Yoshino T, et al. Duration of Adjuvant Doublet Chemotherapy (3 or 6 months) in Patients With High-Risk Stage II Colorectal Cancer. J Clin Oncol. 2021;39(6):631-41. doi:10.1200/JCO.20.01330\u003c/li\u003e\n\u003cli\u003eKim ST, Kim SY, Lee J, et al. Oxaliplatin (3 months v 6 months) With 6 Months of Fluoropyrimidine as Adjuvant Therapy in Patients With Stage II/III Colon Cancer: KCSG CO09-07. J Clin Oncol. 2022;40(33):3868-77. doi:10.1200/JCO.21.02962\u003c/li\u003e\n\u003cli\u003eHaller DG, Tabernero J, Maroun J, et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol. 2011;29(11):1465-71. doi:10.1200/JCO.2010.33.6297\u003c/li\u003e\n\u003cli\u003eGrande C, Quintero G, Candamio S, et al. Biweekly XELOX (capecitabine and oxaliplatin) as first-line treatment in elderly patients with metastatic colorectal cancer. J Geriatr Oncol. 2013;4(2):114-21. doi:10.1016/j.jgo.2013.01.001\u003c/li\u003e\n\u003cli\u003eMatsui T, Nagata N, Hirata K, et al. Bi-weekly Capecitabine-Oxaliplatin (XELOX) plus Bevacizumab as First-line Treatment of Metastatic Colorectal Cancer -The PHOENiX Trial. Anticancer Res. 2016;36(7):3437-43. \u003c/li\u003e\n\u003cli\u003eGrothey A, Sobrero AF, Shields AF, et al. Duration of Adjuvant Chemotherapy for Stage III Colon Cancer. N Engl J Med. 2018;378(13):1177-88. doi:10.1056/NEJMoa1713709\u003c/li\u003e\n\u003cli\u003eChao Y, Hsieh JS, Yeh HT, et al. A multicenter phase II study of biweekly capecitabine in combination with oxaliplatin as first-line chemotherapy in patients with locally advanced or metastatic gastric cancer. Cancer Chemother Pharmacol. 2014;73(4):799-806. doi:10.1007/s00280-014-2407-y\u003c/li\u003e\n\u003cli\u003eArkenau HT, Arnold D, Cassidy J, et al. Efficacy of oxaliplatin plus capecitabine or infusional fluorouracil/leucovorin in patients with metastatic colorectal cancer: a pooled analysis of randomized trials. J Clin Oncol. 2008;26(36):5910-7. doi:10.1200/JCO.2008.16.7759\u003c/li\u003e\n\u003cli\u003eNielson CM, Bylsma LC, Fryzek JP, Saad HA, Crawford J. Relative Dose Intensity of Chemotherapy and Survival in Patients with Advanced Stage Solid Tumor Cancer: A Systematic Review and Meta-Analysis. Oncologist. 2021;26(9):e1609-e18. doi:10.1002/onco.13822\u003c/li\u003e\n\u003cli\u003eKanemitsu Y, Shimizu Y, Mizusawa J, et al. Hepatectomy Followed by mFOLFOX6 Versus Hepatectomy Alone for Liver-Only Metastatic Colorectal Cancer (JCOG0603): A Phase II or III Randomized Controlled Trial. J Clin Oncol. 2021;39(34):3789-99. doi:10.1200/JCO.21.01032\u003c/li\u003e\n\u003cli\u003eKotaka M, Yamanaka T, Yoshino T, et al. Safety data from the phase III Japanese ACHIEVE trial: part of an international, prospective, planned pooled analysis of six phase III trials comparing 3 versus 6 months of oxaliplatin-based adjuvant chemotherapy for stage III colon cancer. ESMO Open. 2018;3(3):e000354. doi:10.1136/esmoopen-2018-000354\u003c/li\u003e\n\u003cli\u003eYoshino T, Yamanaka T, Oki E, et al. Efficacy and Long-term Peripheral Sensory Neuropathy of 3 vs 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Colon Cancer: The ACHIEVE Phase 3 Randomized Clinical Trial. JAMA Oncol. 2019;5(11):1574-81. doi:10.1001/jamaoncol.2019.2572\u003c/li\u003e\n\u003cli\u003eNewton L, Munro T, Hamid M, Shabbir J. Colorectal cancer in the young - outcomes following surgical management? Ann R Coll Surg Engl. 2021;103(9):661-5. doi:10.1308/rcsann.2021.0049\u003c/li\u003e\n\u003cli\u003eEcker BL, Lee J, Saadat LV, et al. Recurrence-free survival versus overall survival as a primary endpoint for studies of resected colorectal liver metastasis: a retrospective study and meta-analysis. Lancet Oncol. 2022;23(10):1332-42. doi:10.1016/S1470-2045(22)00506-X\u003c/li\u003e\n\u003cli\u003eKotani D, Oki E, Nakamura Y, et al. Molecular residual disease and efficacy of adjuvant chemotherapy in patients with colorectal cancer. Nat Med. 2023;29(1):127-34. doi:10.1038/s41591-022-02115-4\u003c/li\u003e\n\u003cli\u003eFaulkner LG, Howells LM, Pepper C, Shaw JA, Thomas AL. The utility of ctDNA in detecting minimal residual disease following curative surgery in colorectal cancer: a systematic review and meta-analysis. Br J Cancer. 2022. doi:10.1038/s41416-022-02017-9\u003c/li\u003e\n\u003cli\u003eAgger E, Jorgren F, Joud A, Lydrup ML, Buchwald P. Negative Prognostic Impact of Tumor Deposits in Rectal Cancer - A National Study Cohort. Ann Surg. 2022. doi:10.1097/SLA.0000000000005755\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Adjuvant chemotherapy, Modified regimen, Thrombocytopenia, Neutropenia, Adverse event","lastPublishedDoi":"10.21203/rs.3.rs-2823745/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2823745/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eAdjuvant CAPOX (capecitabine plus oxaliplatin) provided significant disease-free survival (DFS) benefit in patients with high-risk stage II or stage III colorectal cancer (CRC). Conventional triweekly CAPOX results in 14-38% 3-4 grade hematological toxicity. Modified biweekly CAPOX was observed to be generally well-tolerated in previous studies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e High-risk stage II and stage III post-surgery CRC patients were randomized in the control triweekly group (intravenous infusion of oxaliplatin 130 mg/m2 on day 1 and oral capecitabine 1000 mg/m2, twice daily from d1 to d14) and the experimental biweekly group (intravenous infusion of oxaliplatin 85 mg/m2 on day 1 and oral capecitabine 1000 mg/m2, twice daily from d1 to d10). The primary endpoint was incidence of thrombocytopenia. The secondary endpoint was 18-month DFS rate.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eBetween Jul 25, 2018, and May 14, 2021, 160 patients were 1:1 randomly enrolled and received treatment. The primary endpoint thrombocytopenia occurred 33% and 49% in biweekly and triweekly group (\u003cem\u003eP\u003c/em\u003e=0.02). The second endpoint 18-month DFS in 3-month group was 94.1% in biweekly CAPOX group, and 93.8% in triweekly CPOX group (\u003cem\u003eP\u003c/em\u003e=0.96). Neutropenia was 36% and 51% in biweekly and triweekly group, respectively (\u003cem\u003eP\u003c/em\u003e=0.04). The rate of uncomplete therapy patient was 7% and 15% in biweekly and triweekly group, respectively (\u003cem\u003eP\u003c/em\u003e=0.13).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eBiweekly CAPOX presented significant less thrombocytopenia and neutropenia than triweekly CAPOX regimen. And biweekly CAPOX did not affect the 18-month DFS rate.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial registration: \u003c/strong\u003eFirst registration date: 21/06/2018. ClinicalTials.gov (NCT03564912).\u003c/p\u003e","manuscriptTitle":"Biweekly CAPOX versus Triweekly CAPOX in the adjuvant therapy of post-surgery CRC: a randomized controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-06-26 21:37:45","doi":"10.21203/rs.3.rs-2823745/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"df81e008-17e2-438d-aa11-b7695dbb7cdb","owner":[],"postedDate":"June 26th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-09-18T00:36:20+00:00","versionOfRecord":[],"versionCreatedAt":"2023-06-26 21:37:45","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2823745","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2823745","identity":"rs-2823745","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}