Astragalus polysaccharides improve adjuvant chemotherapy-induced fatigue for patients with early breast cancer

Astragalus polysaccharides improve adjuvant chemotherapy-induced fatigue for patients with early breast cancer | 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 Article Astragalus polysaccharides improve adjuvant chemotherapy-induced fatigue for patients with early breast cancer Wen-Chi Shen, Shin-Cheh Chen, Cheng-Hsu Wang, Chao-Ming Hung, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4336825/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 28 Oct, 2024 Read the published version in Scientific Reports → Version 1 posted 11 You are reading this latest preprint version Abstract Purpose This study aimed to evaluate the effect of Astragalus polysaccharides (PG2) on reducing chemotherapy-induced fatigue (CIF) and toxicity, thereby encouraging compliance to chemotherapy. Methods This was a randomized, placebo-controlled, phase 2 study. Patients with stage II/III early breast cancer planning to undergo adjuvant anthracycline-based chemotherapy were randomly assigned to receive PG2 500 mg or placebo on days 1, 3, and 8 every 21 days. The fatigue global score (FGS) was assessed using the brief fatigue inventory (BFI)-Taiwan. The Breast Cancer-Specific Module of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires-Core30 evaluated the health-related quality of life during the first four cycles of adjuvant chemotherapy. Results Overall, 66 eligible patients were equally randomized into the PG2 and placebo groups between March 01, 2018, and March 09, 2021. The mean change in the FGS and fatigue intensity did not significantly differ between both groups. However, the FGS and fatigue intensity were less aggravated in the first four cycles in the premenopausal-PG2 group than in the placebo group. Conclusion PG2 combined with adjuvant chemotherapy can reduce CIF, insomnia, the negative effect on future perspectives, and improve global health status, especially for premenopausal patients with breast cancer. Trial registration number: NCT03314805 registered on 19/10/2017. Health sciences/Oncology/Cancer Health sciences/Oncology/Cancer/Breast cancer Astragalus polysaccharides cancer-related fatigue chemotherapy-related fatigue breast cancer adjuvant chemotherapy Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 INTRODUCTION Breast cancer is the most commonly diagnosed cancer globally and the leading cause of cancer-related deaths among women [ 1 ]. The cure for breast cancer becomes impossible when it develops into an advanced stage. Therefore, the key factors for enhancing clinical outcomes in breast cancer revolve around early detection, curative resection, and effective adjuvant or neoadjuvant therapy. Substantial improvements have been made in systemic therapies for advanced breast cancer (ABC), including targeted therapy, hormonal therapy, and immunotherapy; however, chemotherapy remains the cornerstone for ABC and early breast cancers (EBC) as well. Adjuvant chemotherapy in EBC reduces recurrence risk and breast cancer mortality [ 2 ]. Nevertheless, chemotherapy is associated with numerous adverse events (AEs), including nausea, vomiting, mucositis, bone marrow suppression, alopecia, peripheral neurotoxicity, and fatigue. Owing to concerns about AEs associated with chemotherapy, many patients hesitate to accept neoadjuvant or adjuvant chemotherapies. Some patients even allow their tumors to progress from EBC to ABC. Therefore, addressing and mitigating AE severity from chemotherapy constitutes crucial aspects of supportive care. Various methods have been implemented to ameliorate AEs from chemotherapy, such as granulocyte colony-stimulating factor for leukopenia, 5-hydroxytryptamine receptor type 3 antagonist for emesis, and modifying the administration schedule from triweekly to weekly. Despite these efforts, fatigue remains a challenge with no good treatment. A nationwide survey in Taiwan revealed that cancer-related fatigue (CRF) was among the most common symptoms for advanced cancers, including breast cancer [ 3 ]. Fatigue is a common AE from neoadjuvant or adjuvant therapy for ABC, either with chemotherapy alone [ 4 , 5 ], in combination with a targeted therapy [ 6 , 7 ], or with immunotherapy, where the incidence can exceed 35% [ 8 , 9 ]. Astragalus polysaccharides (PG2, PhytoHealth Corp., Taiwan) injection has been approved as a pharmacotherapy for treating CRF in patients with advanced cancer in Taiwan. In a pivotal trial, PG2 improved CRF among patients with advanced cancer [ 10 ]. Subsequently, a phase 4 study further validated PG2 efficacy in improving fatigue scores for patients with advanced cancer, especially those with breast cancer [ 11 ]. Numerous translational and clinical studies have provided evidence of the synergistic effects of PG2 with anticancer therapies such as chemotherapy, target therapy, and immunotherapy [ 12 ]. Additionally, studies have highlighted PG2 immunomodulation effects [ 13 ]. In our study, we aimed to evaluate the efficacy of PG2 as a complementary treatment for patients with stage II/III EBC undergoing adjuvant chemotherapy with epirubicin and cyclophosphamide (EC) regimen. The goal was to investigate whether PG2 could reduce chemotherapy-induced fatigue (CIF), minimize toxicity, and enhance compliance to chemotherapy. The primary endpoint involved evaluating the change in the fatigue global score (FGS) using the brief fatigue inventory (BFI)-Taiwan [ 14 ] during the first four EC cycles. The secondary endpoints included chemotherapy dose reductions and delays, the incidence of grade 3/4 hematologic toxicities based on the Common Terminology Criteria for AE 4.03, Eastern Cooperative Oncology Group performance status, and health-related quality of life (HRQL) using the Breast Cancer-Specific Module of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires-Core30 (EORTC QLQ-C30 & BR23) [ 15 ], during the first four EC cycles. MATERIAL AND METHODS Patients This was a double-blind, randomized, and placebo-controlled study design. Patients with stage II/III EBC scheduled for anthracycline-based adjuvant chemotherapy (including EC or EC followed by taxane regimens) underwent screening based on inclusion and exclusion criteria. Only eligible patients were enrolled in this study. Major inclusion criteria included patients: 1) with stage II/III EBC patients, 2) aged above 20 years, 3) scheduled to receive an adjuvant EC-upfront regimen, either six cycles of EC or EC followed by taxane, 4) with adequate bone marrow function (white blood cells ≥ 3000 cells/mm 3 , absolute granulocyte count ≥ 1500 cells/ mm 3 , and platelet count ≥ 100,000 /mm mm 3 ), and 5) with normal liver and kidney function, where serum alanine transaminase and aspartate transaminase were ≤ 2.5 times the upper limit of normal, and bilirubin was ≤ 1.5 times the upper limit of normal. The major exclusion criteria included patients who are pregnant or lactating, with a BFI score exceeding 3, chronic insomnia, chronic fatigue syndrome, uncontrolled active infection, a known severe allergy to Astragalus membranaceus or its major extracts (polysaccharides), and a history of invasive breast cancer or any other malignancy within the past 3 years. The ethics committee of the Institutional Review Board of E-Da Cancer and Chang Gung Memorial Hospitals approved the study design and protocol. This study adheres to the principles outlined in the Declaration of Helsinki and all methods were performed in accordance with the relevant guidelines and regulations. Treatment protocol Patients who met all inclusion criteria and no exclusion criteria were assigned to the treatment or control group based on the randomization schedule. ECs were prescribed a dose of 90 mg/600 mg/m2 every 3 weeks, whereas PG2 or a placebo was administered on days 1, 3, and 8 of each cycle. Four EC cycles were designated for prescription during the elevation period (Fig. 1 ). The Institutional Review Board of all participating hospitals approved the study design, and it was registered at ClinicalTrails.gov with the number NCT03314805. HRQL evaluation We used the BFI-Taiwan [ 14 ] at every return visit to evaluate HRQL. Additionally, HRQL was evaluated [ 15 ] on days 1 and 8 of every cycle using the EORTC QLQ-C30 & BR23 (Fig. 1 ). CIF was assessed through a validated questionnaire derived from the BFI-Taiwan. Two main categories were presented: FGS and fatigue intensity. Each category included several items. The “FGS” was the arithmetic mean of all nine items (score, 0–10). The “fatigue intensity” was defined as the score reflecting the worst fatigue level in the last 24 hours (BFI item 3) on a 0–10 scale. EORTC QLQ-C30 & BR23 data were transformed to yield scores ranging from 0 to 100 based on the EORTC scoring manual. A higher score represented a better quality of life or a higher level of symptoms. Efficacy of data presentation and statistical analysis methods The baseline clinical findings, laboratory data, and performance status were evaluated at the beginning of the study before initiating treatment. Demographic and baseline characteristics were presented for each treatment group. Summary statistics, including mean, median, standard deviation (SD), minimum, and maximum, were provided for continuous variables, such as age. A two-sample t-test or Wilcoxon rank-sum test was used for continuous variables based on whether the data follows or violates the normal distribution, respectively. Categorical data, such as sex, were expressed using frequencies and proportions. Fisher's exact test was utilized to compare the difference in proportions between groups when the sample size was small. Alternatively, a chi-square test was employed. This study included three populations: the intention-to-treat (ITT), including the participants who met the eligibility criteria, took at least one study drug treatment, and were assessed using BFI at least once; the per-protocol (PP) population, including the evaluable participants who met the compliance criteria, defined as receiving a minimum of 75% of the prescribed study drug administration (nine doses) during the treatment period, and without major protocol deviations in the first four EC treatment cycles; the safety populations, comprising the participants who received at least one study drug treatment. Safety evaluation All AEs were evaluated using the Common Terminology Criteria for AEs 4.03 and reported throughout the study. The severity of AE and its relationship to the study drug was summarized. Additionally, changes from the baseline of all laboratory variables were summarized. RESULTS Participant disposition Overall, 67 patients were enrolled across five hospitals in Taiwan from March 01, 2018, to March 09, 2021. Among these, 66 were eligible and equally randomized into the PG2 and placebo groups (n = 33 in each group). At the end of the study, 30 participants (90.9%) in each group completed the study. Three participants (9.1%) from each group withdrew prematurely from the study by using the withdrawal of consent (two in the PG2 group and three in the placebo group) and by the decision of the investigator (one in the PG2 group). All 66 participants were included in the ITT and safety populations. The PP population of the PG2 and placebo groups comprised 29 and 31 participants, respectively (Fig. 2 ). Demographics and patients’ characteristics Most disease characteristics were comparable among the patients, except for the menopausal status, which significantly differed between the groups. The PG2 group enrolled more menopausal participants than the placebo group, accounting for 60.6% vs. 36.4% (P = 0.049*) and 62.1% vs. 35.5% (P = 0.039*) in the ITT/safety and PP populations, respectively (Table 1 ). Except for this, no other significant difference in demographics was observed. In the ITT/safety population, the mean age (± SD) of the PG2 group was 53.6 ± 10.87 years, whereas that of the placebo group was 49.2 ± 10.00 years. The mean body mass index (± SD) of the PG2 group was 26.3 ± 4.51 kg/m 2 , while that of the placebo group was 24.4 ± 4.35 kg/m 2 . Similar data were observed in the PP population. Table 1 Patients’ Characteristics Characteristics PG2 a (n = 33) Placebo (n = 33) P-value Age (year) Mean ± SD 53.6 ± 10.87 49.2 ± 10.00 0.079 BMI (kg/m 2 ) Mean ± SD 26.3 ± 4.51 24.4 ± 4.35 0.100 Baseline ECOG b status 0 30 (90.9) 31 (93.9) > 0.999 1 3 (9.1) 2 (6.1) Histologic subtype, n (%) Ductal 27 (81.8) 26 (78.8) 0.201 Lobular 6 (18.2) 3 (9.1) Unknown 0 (0.0) 4 (12.1) Menopausal status, n (%) Premenopausal 13 (39.4) 21 (63.6) 0.049 Postmenopausal 20 (60.6) 12 (36.4) Molecular type, n (%) TNBC c , n (%) 2 (6.9) 1 (3.0) > 0.999 HR + d /HER2 e -, n (%) 17 (51.5) 18 (54.5) HER2 + f , n (%) 14 (42.4) 14 (42.4) Baseline BFI g fatigue score Mean ± SD h 0.3 ± 0.60 0.4 ± 0.63 0.373 Surgical type, n (%) Conservative 3 (9.1) 1 (3.0) 0.420 Mastectomy 29 (87.9) 32 (97.0) Unknown 1 (3.0) 0 (0.0) Radiotherapy, n (%) 12 (36.4) 10 (30.3) 0.602 a PG2, Astragalus polysaccharides; b ECOG, Eastern Cooperative Oncology Group; c TNBC, Triple-negative breast cancer; d HR+, hormone receptor-positive; e HER2-, human epidermal growth factor receptor 2-negative; f HER2+, human epidermal growth factor receptor 2-positive; g BFI, brief fatigue inventory; h SD, standard deviation. Efficacy Primary endpoints: Overall, no significant difference was observed in the mean change in FGS and fatigue intensity between the ITT groups, with both groups displaying an aggravating trend in FGS and fatigue intensity, demonstrating a significant increase in both groups. In the PG2 group, the mean FGS increased by 0.6–2.0 from baseline within the initial four cycles, whereas in the placebo group, the mean FGS increased by 0.2–1.9 within the same period. Similarly, mean fatigue intensity for the PG2 group increased by 0.5–2.2 from baseline within the initial four cycles, whereas mean fatigue intensity for the placebo group increased by -0.1–2.3 within the same period (Fig. 3 (a) and 3(b)). The PP population yielded results similar to those of the ITT population (data not shown). We observed a lower proportion of patients experiencing grade 3/4 neutropenia from cycles 1–4 in the PG2 group compared with the placebo group (87.9% vs. 93.9% in the ITT population and 93.1% vs. 100.0% in the PP population). The incidence of grade 3/4 neutropenia was comparable between the study groups (Table 2 ). Table 2 Incidence of Grade 3/4 Neutropenia from Cycle 1 to 4 Neutropenia, n (%) Total Cycle 1–4 PG2 a Placebo P-value ITT b N = 33 N = 33 Grade 3 26 (78.8) 29 (87.9) 0.159 Grade 4 26 (78.8) 25 (75.8) 0.616 Grade 3/4 29 (87.9) 31 (93.9) 0.195 PP c N = 29 N = 31 Grade 3 24 (82.8) 29 (93.5) 0.096 Grade 4 24 (82.8) 25 (80.6) 0.584 Grade 3/4 27 (93.1) 31 (100.0) 0.071 a PG2, Astragalus polysaccharides; b ITT, intention-to-treat; c PP, per-protocol. Secondary endpoints: The incidence of participants with grade 3/4 hematologic toxicities, chemotherapy dose reductions, treatment delays, or granulocyte colony-stimulating factor treatment from cycles 1–4 did not significantly differ among the study groups. HRQL was evaluated using the EORTC QLQ-C30 and BR23 questionnaires and Eastern Cooperative Oncology Group. Additionally, the results revealed no significant difference when comparing the study and control groups in the ITT and PP populations. The result of HRQL is shown in the Fig. 3 (c). Subgroup analysis: The subgroup analysis based on menopausal status revealed significant results for premenopausal patients. In the ITT population, the FGS and fatigue intensity were less aggravated in the initial four EC cycles in the premenopausal-PG2 group than in the premenopausal-placebo group (Fig. 4 ). Examining the results of EORTC-QLQ C30 and BR23 among premenopausal patients, those using PG2 reported a better condition of global health status and future perspective, alongside lower fatigue and insomnia burden during the first four EC cycles than those using placebo (Fig. 5 ). The PP population yielded similar results with the ITT population (data not shown). Safety All reported AEs were collected and analyzed during the study. The safety outcomes between the PG2 and placebo groups were comparable. Overall, 1866 AEs were reported in 66 participants, with the majority judged as chemotherapy-related (89.6%, 1671/1866). Severe AE incidences for the PG2 and placebo groups were 22.2% (218/982) and 21.3% (188/884), respectively. Only seven AEs were causally related to PG2 treatment, including pyrexia (two participants), adverse drug reactions, cold, hypersensitivity, rash, and urticaria (one participant for each AE). No AEs led to study discontinuation or death. PG2 was considered tolerable by the participants with breast cancers. DISCUSSION In this study, the primary endpoint, encompassing changes in FGS and fatigue intensity, was similar in both treatment groups. The significance of FGS and fatigue intensity change from baseline in the premenopausal groups emerged from cycles 1 through 4, implying the observable efficacy of PG2 in the premenopausal individuals. The EORTC QLQ-C30 and BR23 questionnaires surveyed the HRQL of the participants. Among the collected survey data, the deterioration of fatigue, insomnia, future perspective, and global health status were reduced during chemotherapy with the use of PG2 for premenopausal women. This result can also be supported by the fatigue domain of EORTC QLQ-C30, where the score for the placebo group increased from below 20 to over 30, whereas the score for the PG2 group remained around 20 throughout the cycles. The trend in the change in fatigue score suggests that PG2 could reduce CIF for premenopausal participants. As menopausal status may be a factor that influences the results, compared with the 36.4% of participants in the placebo group, 60.6% in the PG2 group were postmenopausal, potentially influencing these endpoints. A positive trend was observed in the PG2 group towards the future perspective. This may be linked to the overall outcomes of fatigue, global health status, and insomnia with the PG2 complementary treatment. PG2 is a drug therapy for relieving moderate-to-severe fatigue among patients with cancer. This study suggests that PG2 may have additional efficacy in preventing and reducing CIF severity among patients with breast cancer, particularly premenopausal patients. PG2 can assist patients in maintaining normal daily activities, caring for family, managing job responsibilities during chemotherapy, and maintaining daily activities. These factors are important for overall well-being and social-economic functions. Our previous studies, which focused on patients with advanced cancer who might or might not have received chemotherapy at the time of the study, demonstrated that PG2 could improve patients' CRF, especially in those with breast cancer. No definite difference existed between premenopausal and postmenopausal status in those trials. In contrast, all patients in our trial were disease-free and undergoing chemotherapy, the etiology of fatigue differed from that in the previous trials. Furthermore, the incidence of grade 3/4 neutropenia and other hematologic toxicities increased as the cycle progressed, with no significant difference observed between both study groups. This result suggests that PG2 has no effect on the incidence of chemotherapy-induced hematologic toxicities under the current treatment schedule. The two treatment groups exhibited comparable results in secondary outcomes such as chemotherapy dose reduction, treatment delays, and granulocyte colony-stimulating factor consumption. Based on these findings, the PG2 combination did not interfere with chemotherapy treatment or enhance toxicities in patients with breast cancer. Additionally, PG2 was safe and well-tolerated by patients. AEs were mostly mild, manageable, and unrelated to PG2. The PG2-related AEs included pyrexia, adverse drug reactions, cold, hypersensitivity, rash, and urticaria, which were the known safety profiles of PG2. CONCLUSION Our results indicate comparable efficacy between PG2 and placebo, possibly influenced by the menopausal status of the participants. Subsequently, a subgroup analysis was conducted to evaluate the influence of menopausal status on PG2 efficacy. PG2 effects, including reduced CIF and insomnia, mitigated negative effects on future perspectives, and improved global health status, were observed in the premenopausal group compared with the placebo group. The results suggest that PG2 may have additional efficacy in preventing and reducing the severity of CIF among premenopausal patients undergoing adjuvant anthracycline-based chemotherapy. PG2 could assist these patients in maintaining normal daily activities, caring for family, and managing job responsibilities during chemotherapy. Furthermore, patients undergoing cancer chemotherapy and treated with PG2 might be better positioned to complete their chemotherapy, alleviating concerns about their future health. Finally, treatment with 500 mg of PG2 for 3 days per cycle for four EC chemotherapy cycles was safe and tolerable among patients with breast cancer. Abbreviations Abbreviations Definition s ABC Advanced breast cancer AE Adverse event BFI Brief fatigue inventory CIF Chemotherapy-induced fatigue CRF Cancer-related fatigue EC Epirubicin and cyclophosphamide ECOG Eastern Cooperative Oncology Group EBC Early breast cancer EORTC QLQ-C30 and BR23 Breast cancer-specific module of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires－Core30 FGS Fatigue Global Score HRQL Health-related Quality of Life ITT Intention-to-treat PG2 Astragalus polysaccharides PP Per-protocol SD Standard deviation Declarations Funding This work was supported by PhytoHealth Co. Competing interests The authors have no relevant financial or non-financial interests to disclose. Author contributions Material preparation: S-C.C, C-M.H, M-T.P, C-T.L, Y-S.C, W-L.K, H-H.C, K-Y.Y, T-H.W, C-F.W, P-H.C, Y-M.H, C-C.Y, C-H.L Conceptualization: C-H.W, K-M.R Writing: W-C.S Writing review and editing: K-M.R Data availability The analyzed data in this study are available from the corresponding author upon reasonable request. Ethics approval The approval was granted by the Ethics Committee of the Institutional Review Board of E-Da Cancer Hospital and Chang Gung Memorial Hospitals. This study adheres to the principles outlined in the Declaration of Helsinki and all methods were performed in accordance with the relevant guidelines and regulations. Consent to participate Informed consent was obtained from all individual participants included in the study. Consent to publish The authors affirm that human research participants provided informed consent for publication. 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Chang","email":"","orcid":"","institution":"Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, Keelung City","correspondingAuthor":false,"prefix":"","firstName":"Yueh-Shih","middleName":"","lastName":"Chang","suffix":""},{"id":304567216,"identity":"1802f16e-0957-433f-8377-b696f56a9094","order_by":7,"name":"Wen-Ling Kuo","email":"","orcid":"","institution":"Department of General Surgery, Chang Gung Memorial Hospital, Taipei, Taipei City","correspondingAuthor":false,"prefix":"","firstName":"Wen-Ling","middleName":"","lastName":"Kuo","suffix":""},{"id":304567217,"identity":"4ece96ff-9e0d-42a1-a3f9-9c588c81a295","order_by":8,"name":"Hsu-Huan Chou","email":"","orcid":"","institution":"Department of General Surgery, Chang Gung Memorial Hospital, Taipei, Taipei City","correspondingAuthor":false,"prefix":"","firstName":"Hsu-Huan","middleName":"","lastName":"Chou","suffix":""},{"id":304567218,"identity":"aa6617ce-f1c0-4db1-b6a3-a5d8d071f989","order_by":9,"name":"Kun-Yun Yeh","email":"","orcid":"","institution":"Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, Keelung City","correspondingAuthor":false,"prefix":"","firstName":"Kun-Yun","middleName":"","lastName":"Yeh","suffix":""},{"id":304567219,"identity":"7f3b3912-a06a-44a1-9795-6c19593cfeef","order_by":10,"name":"Tsung-Han Wu","email":"","orcid":"","institution":"Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, Keelung City","correspondingAuthor":false,"prefix":"","firstName":"Tsung-Han","middleName":"","lastName":"Wu","suffix":""},{"id":304567220,"identity":"5b56e435-0580-4052-875d-a774d2a99473","order_by":11,"name":"Chun-Feng Wu","email":"","orcid":"","institution":"Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, Keelung City","correspondingAuthor":false,"prefix":"","firstName":"Chun-Feng","middleName":"","lastName":"Wu","suffix":""},{"id":304567221,"identity":"9e88de0e-3bdb-49ae-96dc-92108c74e1ea","order_by":12,"name":"Pei-Hung Chang","email":"","orcid":"","institution":"Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, Keelung City","correspondingAuthor":false,"prefix":"","firstName":"Pei-Hung","middleName":"","lastName":"Chang","suffix":""},{"id":304567222,"identity":"c0dd60b0-1fd1-476c-ac15-80f655d11550","order_by":13,"name":"Yen-Min Huang","email":"","orcid":"","institution":"Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, Keelung City","correspondingAuthor":false,"prefix":"","firstName":"Yen-Min","middleName":"","lastName":"Huang","suffix":""},{"id":304567223,"identity":"ca5127a6-0ce7-484c-86eb-63e52e437e26","order_by":14,"name":"Chi-Chang Yu","email":"","orcid":"","institution":"Department of General Surgery, Chang Gung Memorial Hospital, Taipei, Taipei City","correspondingAuthor":false,"prefix":"","firstName":"Chi-Chang","middleName":"","lastName":"Yu","suffix":""},{"id":304567224,"identity":"07f010ea-e63c-478b-acf1-591192854f23","order_by":15,"name":"Chun-Hui Lee","email":"","orcid":"","institution":"Department of Surgery, Chang Gung Memorial Hospital, Keelung, Keelung City","correspondingAuthor":false,"prefix":"","firstName":"Chun-Hui","middleName":"","lastName":"Lee","suffix":""},{"id":304567226,"identity":"ab84e710-60f4-4f26-979d-dbf0ef9885d2","order_by":16,"name":"Kun-Ming Rau","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxklEQVRIiWNgGAWjYBACCRDB+MdGDkQfeEC8loY0Y7CWBBK0HE5sADGI0iI57ezDz7w7DqfPDzv8EGiLnZxuAwEt0tLpxtK8Z9JzN95OMwBqSTY2O0BAi5x0GoM0D5t17sbZCSAtBxK3EaGF+TcPG3O64ez0D8RpkZZOY5PmbXNOkJfOIdIWydlpbJZzzqQZbpDOKTiQYECEXyRupzHfeFNhIy8/O33zhw8VdnIEtcCBAVilAbHKQUC+gRTVo2AUjIJRMKIAANUbQetQ8l8tAAAAAElFTkSuQmCC","orcid":"","institution":"Department of Hematology-Oncology, E-Da Cancer Hospital, Kaohsiung City","correspondingAuthor":true,"prefix":"","firstName":"Kun-Ming","middleName":"","lastName":"Rau","suffix":""}],"badges":[],"createdAt":"2024-04-28 07:57:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4336825/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4336825/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-024-76627-z","type":"published","date":"2024-10-28T16:20:27+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":57431343,"identity":"4f064e1f-b268-4722-9156-d45450960184","added_by":"auto","created_at":"2024-05-30 14:58:16","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":4466480,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart of screening, treatment, and follow-up\u003c/p\u003e","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4336825/v1/4917cb6733fde69600053c5f.jpg"},{"id":57429878,"identity":"ebd142e9-773f-42f9-8bde-ccee764a33c9","added_by":"auto","created_at":"2024-05-30 14:50:16","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":2942411,"visible":true,"origin":"","legend":"\u003cp\u003eRandomization, treatment assignments, and follow-up\u003c/p\u003e\n\u003cp\u003eITT intention-to-treat; PG2, \u003cem\u003eAstragalus \u003c/em\u003ePolysaccharides; PP, per-protocol\u003c/p\u003e","description":"","filename":"Fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4336825/v1/785caa79c279246ffdfec503.jpg"},{"id":57429879,"identity":"9110b3d3-9a4e-4f4f-8e2d-e41d33d96bb5","added_by":"auto","created_at":"2024-05-30 14:50:16","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":5407946,"visible":true,"origin":"","legend":"\u003cp\u003eTime-dependent change in BFI fatigue scores and mean EORTC QLQ-C30 Global health status/QoL scores in the two groups at the end of cycle 4 for the ITT population\u003c/p\u003e\n\u003cp\u003ea. Fatigue global score b. Fatigue intensity c. Global health status/QoL\u003c/p\u003e\n\u003cp\u003eBFI, brief fatigue inventory; PG2, \u003cem\u003eAstragalus\u003c/em\u003ePolysaccharides\u003c/p\u003e\n\u003cp\u003e*represents the statistical significance between the groups at each time point\u003c/p\u003e","description":"","filename":"Fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4336825/v1/7ecc19e6abae7041157bd9ac.jpg"},{"id":57429875,"identity":"b701f129-36bf-40ba-814e-7520c2ee7696","added_by":"auto","created_at":"2024-05-30 14:50:16","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":3213442,"visible":true,"origin":"","legend":"\u003cp\u003eTime-dependent change in BFI fatigue scores in the two groups at the end of cycle 4 for the premenopausal ITT population\u003c/p\u003e\n\u003cp\u003eBFI, brief fatigue inventory, PG2, \u003cem\u003eAstragalus \u003c/em\u003epolysaccharides\u003c/p\u003e\n\u003cp\u003e*represents the statistical significance between the groups at each time point\u003c/p\u003e","description":"","filename":"Fig4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4336825/v1/d4f6d4abd0b4647a66e81cd8.jpg"},{"id":57429877,"identity":"9a4fb8b8-0ae9-4946-b3e9-c7414b9ad054","added_by":"auto","created_at":"2024-05-30 14:50:16","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":6202659,"visible":true,"origin":"","legend":"\u003cp\u003eTime-dependent in EORTC QLQ-C30 \u0026amp; Br23 scores in the two groups at the end of cycle 4 for the premenopausal ITT population\u003c/p\u003e\n\u003cp\u003ea. Global health status/QoL b. Future perspective c. Fatigue d. Insomnia\u003c/p\u003e\n\u003cp\u003ePG2, \u003cem\u003eAstragalus\u003c/em\u003e polysaccharides\u003c/p\u003e\n\u003cp\u003e*represents the statistical significance between the groups at each time point\u003c/p\u003e","description":"","filename":"Fig5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4336825/v1/6c077e8aade18927bf3217da.jpg"},{"id":68207135,"identity":"3de0b0db-7324-4f74-b4c0-3d55e0db0673","added_by":"auto","created_at":"2024-11-04 16:35:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":22887170,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4336825/v1/be6ef659-48d8-4545-81d0-3aa368f21e6a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Astragalus polysaccharides improve adjuvant chemotherapy-induced fatigue for patients with early breast cancer","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eBreast cancer is the most commonly diagnosed cancer globally and the leading cause of cancer-related deaths among women [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The cure for breast cancer becomes impossible when it develops into an advanced stage. Therefore, the key factors for enhancing clinical outcomes in breast cancer revolve around early detection, curative resection, and effective adjuvant or neoadjuvant therapy.\u003c/p\u003e \u003cp\u003eSubstantial improvements have been made in systemic therapies for advanced breast cancer (ABC), including targeted therapy, hormonal therapy, and immunotherapy; however, chemotherapy remains the cornerstone for ABC and early breast cancers (EBC) as well. Adjuvant chemotherapy in EBC reduces recurrence risk and breast cancer mortality [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Nevertheless, chemotherapy is associated with numerous adverse events (AEs), including nausea, vomiting, mucositis, bone marrow suppression, alopecia, peripheral neurotoxicity, and fatigue.\u003c/p\u003e \u003cp\u003eOwing to concerns about AEs associated with chemotherapy, many patients hesitate to accept neoadjuvant or adjuvant chemotherapies. Some patients even allow their tumors to progress from EBC to ABC. Therefore, addressing and mitigating AE severity from chemotherapy constitutes crucial aspects of supportive care.\u003c/p\u003e \u003cp\u003eVarious methods have been implemented to ameliorate AEs from chemotherapy, such as granulocyte colony-stimulating factor for leukopenia, 5-hydroxytryptamine receptor type 3 antagonist for emesis, and modifying the administration schedule from triweekly to weekly. Despite these efforts, fatigue remains a challenge with no good treatment.\u003c/p\u003e \u003cp\u003eA nationwide survey in Taiwan revealed that cancer-related fatigue (CRF) was among the most common symptoms for advanced cancers, including breast cancer [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Fatigue is a common AE from neoadjuvant or adjuvant therapy for ABC, either with chemotherapy alone [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], in combination with a targeted therapy [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], or with immunotherapy, where the incidence can exceed 35% [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e\u003cem\u003eAstragalus\u003c/em\u003e polysaccharides (PG2, PhytoHealth Corp., Taiwan) injection has been approved as a pharmacotherapy for treating CRF in patients with advanced cancer in Taiwan. In a pivotal trial, PG2 improved CRF among patients with advanced cancer [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Subsequently, a phase 4 study further validated PG2 efficacy in improving fatigue scores for patients with advanced cancer, especially those with breast cancer [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNumerous translational and clinical studies have provided evidence of the synergistic effects of PG2 with anticancer therapies such as chemotherapy, target therapy, and immunotherapy [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Additionally, studies have highlighted PG2 immunomodulation effects [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our study, we aimed to evaluate the efficacy of PG2 as a complementary treatment for patients with stage II/III EBC undergoing adjuvant chemotherapy with epirubicin and cyclophosphamide (EC) regimen. The goal was to investigate whether PG2 could reduce chemotherapy-induced fatigue (CIF), minimize toxicity, and enhance compliance to chemotherapy. The primary endpoint involved evaluating the change in the fatigue global score (FGS) using the brief fatigue inventory (BFI)-Taiwan [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] during the first four EC cycles. The secondary endpoints included chemotherapy dose reductions and delays, the incidence of grade 3/4 hematologic toxicities based on the Common Terminology Criteria for AE 4.03, Eastern Cooperative Oncology Group performance status, and health-related quality of life (HRQL) using the Breast Cancer-Specific Module of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires-Core30 (EORTC QLQ-C30 \u0026amp; BR23) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], during the first four EC cycles.\u003c/p\u003e"},{"header":"MATERIAL AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eThis was a double-blind, randomized, and placebo-controlled study design. Patients with stage II/III EBC scheduled for anthracycline-based adjuvant chemotherapy (including EC or EC followed by taxane regimens) underwent screening based on inclusion and exclusion criteria. Only eligible patients were enrolled in this study.\u003c/p\u003e \u003cp\u003eMajor inclusion criteria included patients: 1) with stage II/III EBC patients, 2) aged above 20 years, 3) scheduled to receive an adjuvant EC-upfront regimen, either six cycles of EC or EC followed by taxane, 4) with adequate bone marrow function (white blood cells \u0026ge; 3000 cells/mm\u003csup\u003e3\u003c/sup\u003e, absolute granulocyte count \u0026ge; 1500 cells/ mm\u003csup\u003e3\u003c/sup\u003e, and platelet count \u0026ge; 100,000 /mm mm\u003csup\u003e3\u003c/sup\u003e), and 5) with normal liver and kidney function, where serum alanine transaminase and aspartate transaminase were \u0026le; 2.5 times the upper limit of normal, and bilirubin was \u0026le; 1.5 times the upper limit of normal. The major exclusion criteria included patients who are pregnant or lactating, with a BFI score exceeding 3, chronic insomnia, chronic fatigue syndrome, uncontrolled active infection, a known severe allergy to \u003cem\u003eAstragalus membranaceus\u003c/em\u003e or its major extracts (polysaccharides), and a history of invasive breast cancer or any other malignancy within the past 3 years.\u003c/p\u003e \u003cp\u003e The ethics committee of the Institutional Review Board of E-Da Cancer and Chang Gung Memorial Hospitals approved the study design and protocol. This study adheres to the principles outlined in the Declaration of Helsinki and all methods were performed in accordance with the relevant guidelines and regulations.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eTreatment protocol\u003c/h2\u003e \u003cp\u003ePatients who met all inclusion criteria and no exclusion criteria were assigned to the treatment or control group based on the randomization schedule. ECs were prescribed a dose of 90 mg/600 mg/m2 every 3 weeks, whereas PG2 or a placebo was administered on days 1, 3, and 8 of each cycle. Four EC cycles were designated for prescription during the elevation period (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The Institutional Review Board of all participating hospitals approved the study design, and it was registered at ClinicalTrails.gov with the number NCT03314805.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eHRQL evaluation\u003c/h2\u003e \u003cp\u003eWe used the BFI-Taiwan [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] at every return visit to evaluate HRQL. Additionally, HRQL was evaluated [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] on days 1 and 8 of every cycle using the EORTC QLQ-C30 \u0026amp; BR23 (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). CIF was assessed through a validated questionnaire derived from the BFI-Taiwan. Two main categories were presented: FGS and fatigue intensity. Each category included several items. The \u0026ldquo;FGS\u0026rdquo; was the arithmetic mean of all nine items (score, 0\u0026ndash;10). The \u0026ldquo;fatigue intensity\u0026rdquo; was defined as the score reflecting the worst fatigue level in the last 24 hours (BFI item 3) on a 0\u0026ndash;10 scale. EORTC QLQ-C30 \u0026amp; BR23 data were transformed to yield scores ranging from 0 to 100 based on the EORTC scoring manual. A higher score represented a better quality of life or a higher level of symptoms.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eEfficacy of data presentation and statistical analysis methods\u003c/h2\u003e \u003cp\u003eThe baseline clinical findings, laboratory data, and performance status were evaluated at the beginning of the study before initiating treatment. Demographic and baseline characteristics were presented for each treatment group.\u003c/p\u003e \u003cp\u003e Summary statistics, including mean, median, standard deviation (SD), minimum, and maximum, were provided for continuous variables, such as age. A two-sample t-test or Wilcoxon rank-sum test was used for continuous variables based on whether the data follows or violates the normal distribution, respectively.\u003c/p\u003e \u003cp\u003eCategorical data, such as sex, were expressed using frequencies and proportions. Fisher's exact test was utilized to compare the difference in proportions between groups when the sample size was small. Alternatively, a chi-square test was employed.\u003c/p\u003e \u003cp\u003eThis study included three populations: the intention-to-treat (ITT), including the participants who met the eligibility criteria, took at least one study drug treatment, and were assessed using BFI at least once; the per-protocol (PP) population, including the evaluable participants who met the compliance criteria, defined as receiving a minimum of 75% of the prescribed study drug administration (nine doses) during the treatment period, and without major protocol deviations in the first four EC treatment cycles; the safety populations, comprising the participants who received at least one study drug treatment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eSafety evaluation\u003c/h2\u003e \u003cp\u003eAll AEs were evaluated using the Common Terminology Criteria for AEs 4.03 and reported throughout the study. The severity of AE and its relationship to the study drug was summarized. Additionally, changes from the baseline of all laboratory variables were summarized.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eParticipant disposition\u003c/h2\u003e \u003cp\u003eOverall, 67 patients were enrolled across five hospitals in Taiwan from March 01, 2018, to March 09, 2021. Among these, 66 were eligible and equally randomized into the PG2 and placebo groups (n\u0026thinsp;=\u0026thinsp;33 in each group). At the end of the study, 30 participants (90.9%) in each group completed the study. Three participants (9.1%) from each group withdrew prematurely from the study by using the withdrawal of consent (two in the PG2 group and three in the placebo group) and by the decision of the investigator (one in the PG2 group). All 66 participants were included in the ITT and safety populations. The PP population of the PG2 and placebo groups comprised 29 and 31 participants, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eDemographics and patients\u0026rsquo; characteristics\u003c/h2\u003e \u003cp\u003eMost disease characteristics were comparable among the patients, except for the menopausal status, which significantly differed between the groups. The PG2 group enrolled more menopausal participants than the placebo group, accounting for 60.6% vs. 36.4% (P\u0026thinsp;=\u0026thinsp;0.049*) and 62.1% vs. 35.5% (P\u0026thinsp;=\u0026thinsp;0.039*) in the ITT/safety and PP populations, respectively (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Except for this, no other significant difference in demographics was observed. In the ITT/safety population, the mean age (\u0026plusmn;\u0026thinsp;SD) of the PG2 group was 53.6\u0026thinsp;\u0026plusmn;\u0026thinsp;10.87 years, whereas that of the placebo group was 49.2\u0026thinsp;\u0026plusmn;\u0026thinsp;10.00 years. The mean body mass index (\u0026plusmn;\u0026thinsp;SD) of the PG2 group was 26.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.51 kg/m\u003csup\u003e2\u003c/sup\u003e, while that of the placebo group was 24.4\u0026thinsp;\u0026plusmn;\u0026thinsp;4.35 kg/m\u003csup\u003e2\u003c/sup\u003e. Similar data were observed in the PP population.\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\u003ePatients\u0026rsquo; Characteristics\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=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePG2\u003csup\u003ea\u003c/sup\u003e (n\u0026thinsp;=\u0026thinsp;33)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePlacebo (n\u0026thinsp;=\u0026thinsp;33)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eAge (year)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53.6\u0026thinsp;\u0026plusmn;\u0026thinsp;10.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49.2\u0026thinsp;\u0026plusmn;\u0026thinsp;10.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.079\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBMI\u0026nbsp;(kg/m\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.4\u0026thinsp;\u0026plusmn;\u0026thinsp;4.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBaseline ECOG\u003c/b\u003e\u003csup\u003e\u003cb\u003eb\u003c/b\u003e\u003c/sup\u003e \u003cb\u003estatus\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (90.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (93.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (6.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHistologic subtype, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuctal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (81.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (78.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.201\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLobular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (18.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (9.1)\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\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (12.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMenopausal status, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePremenopausal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (39.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (63.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.049\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePostmenopausal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (60.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (36.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMolecular type, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTNBC\u003csup\u003ec\u003c/sup\u003e, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (6.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHR\u0026thinsp;+\u0026thinsp;\u003csup\u003ed\u003c/sup\u003e/HER2\u003csup\u003ee\u003c/sup\u003e-, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (51.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (54.5)\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\u003eHER2\u0026thinsp;+\u0026thinsp;\u003csup\u003ef\u003c/sup\u003e, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (42.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (42.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBaseline BFI\u003c/b\u003e\u003csup\u003e\u003cb\u003eg\u003c/b\u003e\u003c/sup\u003e \u003cb\u003efatigue score\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003csup\u003eh\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.373\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSurgical type, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConservative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.420\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMastectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (87.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32 (97.0)\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\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\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\u003cb\u003eRadiotherapy, n (%)\u003c/b\u003e\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 \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (36.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (30.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.602\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003ea\u003c/sup\u003ePG2, \u003cem\u003eAstragalus\u003c/em\u003e polysaccharides; \u003csup\u003eb\u003c/sup\u003eECOG, Eastern Cooperative Oncology Group; \u003csup\u003ec\u003c/sup\u003eTNBC, Triple-negative breast cancer; \u003csup\u003ed\u003c/sup\u003eHR+, hormone receptor-positive; \u003csup\u003ee\u003c/sup\u003eHER2-, human epidermal growth factor receptor 2-negative; \u003csup\u003ef\u003c/sup\u003eHER2+, human epidermal growth factor receptor 2-positive; \u003csup\u003eg\u003c/sup\u003eBFI, brief fatigue inventory; \u003csup\u003eh\u003c/sup\u003eSD, standard deviation.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eEfficacy\u003c/h2\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003ePrimary endpoints:\u003c/h2\u003e \u003cp\u003eOverall, no significant difference was observed in the mean change in FGS and fatigue intensity between the ITT groups, with both groups displaying an aggravating trend in FGS and fatigue intensity, demonstrating a significant increase in both groups. In the PG2 group, the mean FGS increased by 0.6\u0026ndash;2.0 from baseline within the initial four cycles, whereas in the placebo group, the mean FGS increased by 0.2\u0026ndash;1.9 within the same period. Similarly, mean fatigue intensity for the PG2 group increased by 0.5\u0026ndash;2.2 from baseline within the initial four cycles, whereas mean fatigue intensity for the placebo group increased by -0.1\u0026ndash;2.3 within the same period (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e(a) and 3(b)). The PP population yielded results similar to those of the ITT population (data not shown).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eWe observed a lower proportion of patients experiencing grade 3/4 neutropenia from cycles 1\u0026ndash;4 in the PG2 group compared with the placebo group (87.9% vs. 93.9% in the ITT population and 93.1% vs. 100.0% in the PP population). The incidence of grade 3/4 neutropenia was comparable between the study groups (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\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\u003eIncidence of Grade 3/4 Neutropenia from Cycle 1 to 4\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=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNeutropenia, n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eTotal\u0026nbsp;Cycle\u0026nbsp;1\u0026ndash;4\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePG2\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePlacebo\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eITT\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;33\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\u003eGrade 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (78.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29 (87.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.159\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (78.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25 (75.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.616\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 3/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (87.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (93.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.195\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePP\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;31\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\u003eGrade 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (82.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29 (93.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.096\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (82.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25 (80.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.584\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 3/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (93.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (100.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.071\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003ea\u003c/sup\u003ePG2, \u003cem\u003eAstragalus\u003c/em\u003e polysaccharides; \u003csup\u003eb\u003c/sup\u003eITT, intention-to-treat; \u003csup\u003ec\u003c/sup\u003ePP, per-protocol.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSecondary endpoints:\u003c/h2\u003e \u003cp\u003eThe incidence of participants with grade 3/4 hematologic toxicities, chemotherapy dose reductions, treatment delays, or granulocyte colony-stimulating factor treatment from cycles 1\u0026ndash;4 did not significantly differ among the study groups. HRQL was evaluated using the EORTC QLQ-C30 and BR23 questionnaires and Eastern Cooperative Oncology Group. Additionally, the results revealed no significant difference when comparing the study and control groups in the ITT and PP populations. The result of HRQL is shown in the Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e(c).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eSubgroup analysis:\u003c/h2\u003e \u003cp\u003eThe subgroup analysis based on menopausal status revealed significant results for premenopausal patients. In the ITT population, the FGS and fatigue intensity were less aggravated in the initial four EC cycles in the premenopausal-PG2 group than in the premenopausal-placebo group (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Examining the results of EORTC-QLQ C30 and BR23 among premenopausal patients, those using PG2 reported a better condition of global health status and future perspective, alongside lower fatigue and insomnia burden during the first four EC cycles than those using placebo (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). The PP population yielded similar results with the ITT population (data not shown).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eSafety\u003c/h2\u003e \u003cp\u003eAll reported AEs were collected and analyzed during the study. The safety outcomes between the PG2 and placebo groups were comparable. Overall, 1866 AEs were reported in 66 participants, with the majority judged as chemotherapy-related (89.6%, 1671/1866). Severe AE incidences for the PG2 and placebo groups were 22.2% (218/982) and 21.3% (188/884), respectively. Only seven AEs were causally related to PG2 treatment, including pyrexia (two participants), adverse drug reactions, cold, hypersensitivity, rash, and urticaria (one participant for each AE). No AEs led to study discontinuation or death. PG2 was considered tolerable by the participants with breast cancers.\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this study, the primary endpoint, encompassing changes in FGS and fatigue intensity, was similar in both treatment groups. The significance of FGS and fatigue intensity change from baseline in the premenopausal groups emerged from cycles 1 through 4, implying the observable efficacy of PG2 in the premenopausal individuals. The EORTC QLQ-C30 and BR23 questionnaires surveyed the HRQL of the participants. Among the collected survey data, the deterioration of fatigue, insomnia, future perspective, and global health status were reduced during chemotherapy with the use of PG2 for premenopausal women. This result can also be supported by the fatigue domain of EORTC QLQ-C30, where the score for the placebo group increased from below 20 to over 30, whereas the score for the PG2 group remained around 20 throughout the cycles. The trend in the change in fatigue score suggests that PG2 could reduce CIF for premenopausal participants.\u003c/p\u003e \u003cp\u003eAs menopausal status may be a factor that influences the results, compared with the 36.4% of participants in the placebo group, 60.6% in the PG2 group were postmenopausal, potentially influencing these endpoints. A positive trend was observed in the PG2 group towards the future perspective. This may be linked to the overall outcomes of fatigue, global health status, and insomnia with the PG2 complementary treatment.\u003c/p\u003e \u003cp\u003ePG2 is a drug therapy for relieving moderate-to-severe fatigue among patients with cancer. This study suggests that PG2 may have additional efficacy in preventing and reducing CIF severity among patients with breast cancer, particularly premenopausal patients. PG2 can assist patients in maintaining normal daily activities, caring for family, managing job responsibilities during chemotherapy, and maintaining daily activities. These factors are important for overall well-being and social-economic functions.\u003c/p\u003e \u003cp\u003eOur previous studies, which focused on patients with advanced cancer who might or might not have received chemotherapy at the time of the study, demonstrated that PG2 could improve patients' CRF, especially in those with breast cancer. No definite difference existed between premenopausal and postmenopausal status in those trials. In contrast, all patients in our trial were disease-free and undergoing chemotherapy, the etiology of fatigue differed from that in the previous trials.\u003c/p\u003e \u003cp\u003eFurthermore, the incidence of grade 3/4 neutropenia and other hematologic toxicities increased as the cycle progressed, with no significant difference observed between both study groups. This result suggests that PG2 has no effect on the incidence of chemotherapy-induced hematologic toxicities under the current treatment schedule.\u003c/p\u003e \u003cp\u003eThe two treatment groups exhibited comparable results in secondary outcomes such as chemotherapy dose reduction, treatment delays, and granulocyte colony-stimulating factor consumption. Based on these findings, the PG2 combination did not interfere with chemotherapy treatment or enhance toxicities in patients with breast cancer.\u003c/p\u003e \u003cp\u003eAdditionally, PG2 was safe and well-tolerated by patients. AEs were mostly mild, manageable, and unrelated to PG2. The PG2-related AEs included pyrexia, adverse drug reactions, cold, hypersensitivity, rash, and urticaria, which were the known safety profiles of PG2.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003e Our results indicate comparable efficacy between PG2 and placebo, possibly influenced by the menopausal status of the participants. Subsequently, a subgroup analysis was conducted to evaluate the influence of menopausal status on PG2 efficacy. PG2 effects, including reduced CIF and insomnia, mitigated negative effects on future perspectives, and improved global health status, were observed in the premenopausal group compared with the placebo group.\u003c/p\u003e \u003cp\u003eThe results suggest that PG2 may have additional efficacy in preventing and reducing the severity of CIF among premenopausal patients undergoing adjuvant anthracycline-based chemotherapy. PG2 could assist these patients in maintaining normal daily activities, caring for family, and managing job responsibilities during chemotherapy. Furthermore, patients undergoing cancer chemotherapy and treated with PG2 might be better positioned to complete their chemotherapy, alleviating concerns about their future health.\u003c/p\u003e \u003cp\u003eFinally, treatment with 500 mg of PG2 for 3 days per cycle for four EC chemotherapy cycles was safe and tolerable among patients with breast cancer.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.010452961672474%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAbbreviations\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"67.77003484320558%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDefinition\u003c/strong\u003es\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.2195121951219512%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.010452961672474%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eABC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"67.77003484320558%\" valign=\"top\"\u003e\n \u003cp\u003eAdvanced breast cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.2195121951219512%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.010452961672474%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"67.77003484320558%\" valign=\"top\"\u003e\n \u003cp\u003eAdverse event\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.2195121951219512%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.010452961672474%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eBFI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"67.77003484320558%\" valign=\"top\"\u003e\n \u003cp\u003eBrief fatigue inventory\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.2195121951219512%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.010452961672474%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCIF\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"67.77003484320558%\" valign=\"top\"\u003e\n \u003cp\u003eChemotherapy-induced fatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.2195121951219512%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.010452961672474%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCRF\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"67.77003484320558%\" valign=\"top\"\u003e\n \u003cp\u003eCancer-related fatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.2195121951219512%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.010452961672474%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eEC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"67.77003484320558%\" valign=\"top\"\u003e\n \u003cp\u003eEpirubicin and cyclophosphamide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.2195121951219512%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.010452961672474%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eECOG\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"67.77003484320558%\" valign=\"top\"\u003e\n \u003cp\u003eEastern Cooperative Oncology Group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"1.2195121951219512%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.393298059964728%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eEBC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"68.60670194003528%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eEarly breast cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.393298059964728%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eEORTC QLQ-C30 and BR23\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"68.60670194003528%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eBreast cancer-specific module of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires－Core30\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.393298059964728%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eFGS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"68.60670194003528%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eFatigue\u0026nbsp;Global\u0026nbsp;Score\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.393298059964728%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eHRQL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"68.60670194003528%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eHealth-related Quality of Life\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.393298059964728%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eITT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"68.60670194003528%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eIntention-to-treat\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.393298059964728%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePG2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"68.60670194003528%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eAstragalus\u003c/em\u003e polysaccharides\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.393298059964728%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"68.60670194003528%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003ePer-protocol\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.393298059964728%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"68.60670194003528%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eStandard deviation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by PhytoHealth Co.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\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\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMaterial preparation: S-C.C, C-M.H, M-T.P, C-T.L, Y-S.C, W-L.K, H-H.C, K-Y.Y, T-H.W, C-F.W, P-H.C, Y-M.H, C-C.Y, C-H.L\u003c/p\u003e\n\u003cp\u003eConceptualization: C-H.W, K-M.R\u003c/p\u003e\n\u003cp\u003eWriting: W-C.S\u003c/p\u003e\n\u003cp\u003eWriting review and editing: K-M.R\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe analyzed data in this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe approval was granted by the Ethics Committee of the Institutional Review Board of E-Da Cancer Hospital and Chang Gung Memorial Hospitals. This study adheres to the principles outlined in the Declaration of Helsinki and all methods were performed in accordance with the relevant guidelines and regulations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors affirm that human research participants provided informed consent for publication.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSung H, Ferlay J, Siegel RL, et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209-249. https://doi.org/10.3322/caac.21660\u003c/li\u003e\n\u003cli\u003eBines J, Earl H, Buzaid AC, Saad ED (2014) Anthracyclines and taxanes in the neo/adjuvant treatment of breast cancer: does the sequence matter. Ann Oncol 25:1079-1085. https://doi.org/10.1093/annonc/mdu007\u003c/li\u003e\n\u003cli\u003eRau KM, Shun SC, Chiou TJ, et al (2020) A nationwide survey of fatigue in cancer patients in Taiwan: an unmet need. Jpn J Clin Oncol 50:693-700. https://doi.org/10.1093/jjco/hyaa038\u003c/li\u003e\n\u003cli\u003eGluz O, Kuemmel S, Nitz U, et al (2023) Nab-paclitaxel weekly versus dose-dense solvent-based paclitaxel followed by dose-dense epirubicin plus cyclophosphamide in high-risk HR+/HER2- early breast cancer: results from the neoadjuvant part of the WSG-ADAPT-HR+/HER2- trial. Ann Oncol 34:531-542. https://doi.org/10.1016/j.annonc.2023.04.002\u003c/li\u003e\n\u003cli\u003eYuan P, Kang Y, Ma F, et al (2023) Effect of epirubicin plus paclitaxel vs epirubicin and cyclophosphamide followed by paclitaxel on disease-free survival among patients with operable ERBB2-negative and lymph node-positive breast cancer: a randomized clinical trial. JAMA Netw Open 6:e230122. https://doi.org/10.1001/jamanetworkopen.2023.0122\u003c/li\u003e\n\u003cli\u003eGianni L, Pienkowski T, Im YH, et al (2012) Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13:25-32. https://doi.org/10.1016/S1470-2045(11)70336-9\u003c/li\u003e\n\u003cli\u003eSlamon D, Eiermann W, Robert N, et al (2011) Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 365:1273-1283. https://doi.org/10.1056/NEJMoa0910383\u003c/li\u003e\n\u003cli\u003eMittendorf EA, Zhang H, Barrios CH, et al (2020) Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet 396:1090-1100. https://doi.org/10.1016/S0140-6736(20)31953-X\u003c/li\u003e\n\u003cli\u003eSchmid P, Cortes J, Dent R, et al (2022) Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med 386:556-567. https://doi.org/10.1056/NEJMoa2112651\u003c/li\u003e\n\u003cli\u003eChen HW, Lin IH, Chen YJ, et al (2012) A novel infusible botanically-derived drug, PG2, for cancer-related fatigue: a phase II double-blind, randomized placebo-controlled study. Clin Invest Med 35:E1-E11. https://doi.org/10.25011/cim.v35i1.16100\u003c/li\u003e\n\u003cli\u003eWang CH, Lin CY, Chen JS, et al. (2019) Karnofsky performance status as a predictive factor for cancer-related fatigue treatment with Astragalus polysaccharides (PG2) injection-a double blind, multi-center, randomized phase IV study. Cancers (Basel) 11:128. https://doi.org/10.3390/cancers11020128 \u003c/li\u003e\n\u003cli\u003eDu Y, Wan H, Huang P, Yang J, He Y (2022) A critical review of Astragalus polysaccharides: from therapeutic mechanisms to pharmaceutics. Biomed Pharmacother 147:112654. https://doi.org/10.1016/j.biopha.2022.112654\u003c/li\u003e\n\u003cli\u003eTsao SM, Wu TC, Chen J, Chang F, Tsao T (2021) Astragalus polysaccharide injection (PG2) normalizes the neutrophil-to-lymphocyte ratio in patients with advanced lung cancer receiving immunotherapy. Integr Cancer Ther 20:1534735421995256. https://doi.org/10.1177/1534735421995256\u003c/li\u003e\n\u003cli\u003eLin CC, Chang AP, Chen ML, Cleeland CS, Mendoza TR, Wang XS (2006) Validation of the Taiwanese version of the Brief Fatigue Inventory. J Pain Symptom Manage 32:52-59. https://doi.org/10.1016/j.jpainsymman.2005.12.019\u003c/li\u003e\n\u003cli\u003eChie WC, Chang KJ, Huang CS, Kuo WH (2003) Quality of life of breast cancer patients in Taiwan: validation of the Taiwan Chinese version of the EORTC QLQ-C30 and EORTC QLQ-BR23. Psychooncology 12:729-735. https://doi.org/10.1002/pon.727\u003c/li\u003e\n\u003c/ol\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":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Astragalus polysaccharides, cancer-related fatigue, chemotherapy-related fatigue, breast cancer, adjuvant chemotherapy","lastPublishedDoi":"10.21203/rs.3.rs-4336825/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4336825/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study aimed to evaluate the effect of \u003cem\u003eAstragalus\u003c/em\u003e polysaccharides (PG2) on reducing chemotherapy-induced fatigue (CIF) and toxicity, thereby encouraging compliance to chemotherapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis was a randomized, placebo-controlled, phase 2 study. Patients with stage II/III early breast cancer planning to undergo adjuvant anthracycline-based chemotherapy were randomly assigned to receive PG2 500 mg or placebo on days 1, 3, and 8 every 21 days. The fatigue global score (FGS) was assessed using the brief fatigue inventory (BFI)-Taiwan. The Breast Cancer-Specific Module of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires-Core30 evaluated the health-related quality of life during the first four cycles of adjuvant chemotherapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOverall, 66 eligible patients were equally randomized into the PG2 and placebo groups between March 01, 2018, and March 09, 2021. The mean change in the FGS and fatigue intensity did not significantly differ between both groups. However, the FGS and fatigue intensity were less aggravated in the first four cycles in the premenopausal-PG2 group than in the placebo group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePG2 combined with adjuvant chemotherapy can reduce CIF, insomnia, the negative effect on future perspectives, and improve global health status, especially for premenopausal patients with breast cancer.\u003c/p\u003e\n\u003cp\u003eTrial registration number: NCT03314805 registered on 19/10/2017.\u003c/p\u003e","manuscriptTitle":"Astragalus polysaccharides improve adjuvant chemotherapy-induced fatigue for patients with early breast cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-30 14:50:11","doi":"10.21203/rs.3.rs-4336825/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-09-25T05:10:42+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-24T13:42:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"85674714318089423579970276631761117974","date":"2024-09-14T06:44:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"163383864643911882700542439174848281149","date":"2024-07-25T06:51:53+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-16T20:18:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"102261106437708855454753858213500145185","date":"2024-07-15T16:46:26+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-07-05T12:38:13+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-05T12:02:12+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-05-15T06:33:34+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-15T06:24:39+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-04-28T07:55:42+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7d81547a-d8b3-4f4a-b81b-336a0e239c8c","owner":[],"postedDate":"May 30th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":32153293,"name":"Health sciences/Oncology/Cancer"},{"id":32153294,"name":"Health sciences/Oncology/Cancer/Breast cancer"}],"tags":[],"updatedAt":"2024-11-04T16:28:00+00:00","versionOfRecord":{"articleIdentity":"rs-4336825","link":"https://doi.org/10.1038/s41598-024-76627-z","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2024-10-28 16:20:27","publishedOnDateReadable":"October 28th, 2024"},"versionCreatedAt":"2024-05-30 14:50:11","video":"","vorDoi":"10.1038/s41598-024-76627-z","vorDoiUrl":"https://doi.org/10.1038/s41598-024-76627-z","workflowStages":[]},"version":"v1","identity":"rs-4336825","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4336825","identity":"rs-4336825","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}