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Safety and efficacy of spleen aminopeptide oral lyophilized powder for improving quality of life and immune response in patients with advanced breast cancer: a multicenter, randomized, double-blind, placebo-controlled clinical trial

Safety and efficacy of spleen aminopeptide oral lyophilized powder for improving quality of life... Original article 1067 Safety and efficacy of spleen aminopeptide oral lyophilized powder for improving quality of life and immune response in patients with advanced breast cancer: a multicenter, randomized, double-blind, placebo-controlled clinical trial Jing Wang, Xiao Ma, Kun Shang, Shanshan Wu, Yan Ma, Zhongjun Ma and Bangwei Cao Health-related quality of life (HRQoL) is an important On day 84, the number of CD3, CD4 and CD8 cells were consideration in managing patients. Spleen significantly higher in patients who received SAOLP. aminopeptide oral lyophilized powder (SAOLP) has There were no significant differences in objective been used to enhance cellular immunity in a patient. response rate, disease control rate or BMI. SAOLP may This multicenter, randomized, double-blind, placebo- improve HRQoL and the immune response in patients controlled clinical trial was designed to evaluate the with advanced breast cancer, represents a convenient safety and efficacy of SAOLP for improving HRQoL and safe adjuvant therapy. Anti-Cancer Drugs 32: in patients with breast cancer. Patients diagnosed 1067–1075 Copyright © 2021 The Author(s). Published with advanced breast cancer were included, and were by Wolters Kluwer Health, Inc. administered SAOLP or placebo 4 mg qd for two cycles. Anti-Cancer Drugs 2021, 32:1067–1075 The primary endpoint was improvement in HRQoL on Keywords: breast cancer, clinical trial, immune response, quality of life, day 42 measured by the EORTC QLQ-C30 and EORTC spleen aminopeptide oral lyophilized powder QLQ-BR23. Secondary endpoints included immunologic Department of Oncology, Beijing Friendship Hospital, Capital Medical University, function, improvement in HRQoL on day 21 and 84, Beijing, China objective response rate, disease control rate, BMI and Correspondence to Bangwei Cao, PhD, Department of Oncology, Beijing adverse events. On day 42, on the EORTC QLQ-C30 Friendship Hospital, Capital Medical University, #95 Yong An Road, Xicheng or EORTC QLQ-BR23, scores on the functional scales District, Beijing 100050, China Tel: +86 010 63139321; fax: +86 010 63139321; and QoL scale were significantly higher and scores on e-mail: oncology@ccmu.edu.cn symptom scales were significantly lower in patients Received 31 March 2021 Revised form accepted 30 May 2021 who received SAOLP compared to placebo (P < 0.05). Introduction (92%) and breast cancer (women) (90%) [1] During In the United States (US), in 2020, there will be 2012–2016, the incidence of breast cancer in the US approximately 1  806  590 new cancer diagnoses and increased 0.3% per year, driven by an increased inci- 606 520 cancer-related deaths [1]. On 1 January 2030, dence of local stage and hormone receptor-positive an estimated 22.1 million Americans will be living disease [3]. with a cancer history, an increase from the 16.9 million Treatment for breast cancer includes surgery, radio- Americans who were living with a cancer history on 1 therapy and cytotoxic and endocrine drugs. Clinically, January 2019. In the US, in 2019, the most prevalent the goal of breast cancer treatment is to remove all vis- cancers among males included prostate (3  650  030), ible cancer and manage the disease over the long term. colon and rectum (776  120), and melanoma of the Patient health-related quality of life (HRQoL), defined skin (684 470), and the most prevalent cancers among as the patient-perceived psychosocial, emotional females included breast (3  861  520), uterine corpus and physical outcomes of medical intervention [4], is (807  860), and colon and rectum (768  650). Among another important aspect of breast cancer treatment cancer survivors in the US in 2019, 56% received their [5,6]. In particular, patient HRQoL should be consid- diagnosis during the last decade, and 64% were aged ered when a treatment approach is unlikely to improve ≥65 years [2]. Across all stages, survival rates were high- survival, as in some metastatic cancers. The American est for prostate cancer (98%), melanoma of the skin Society of Clinical Oncology, National Institutes of This is an open-access article distributed under the terms of the Creative Health and the National Cancer Institute recommend Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY- that patients should only be exposed to treatments NC-ND), where it is permissible to download and share the work provided it is LWW without evidence of survival benefits if they can reason- properly cited. The work cannot be changed in any way or used commercially without permission from the journal. ably expect an improvement in HRQoL. Accordingly, 0959-4973 Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. DOI: 10.1097/CAD.0000000000001109 Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 1068 Anti-Cancer Drugs 2021, Vol 32 No 10 HRQoL evaluation is increasingly recognized as an Treatment important outcome measure in clinical trials [7]. Breast cancer patients received standard therapy recom- mended by the NCCN Clinical Practice Guidelines in Spleen aminopeptide oral lyophilized powder (SAOLP), Oncology: Breast Cancer. Patients were administered which consists of peptides and nucleotides extracted from SAOLP or placebo (Fu Ketuo, Zhejiang Feng; State fresh pig spleen [8], has been used to enhance cellular Medical Permit No. H20068132) 4 mg qd po. on the first immunity and immune homeostasis in pediatric patients day of chemotherapy for two cycles. SAOLP was manufac- with respiratory infection [9] or immune disorders [10,11], tured according to the Standard for Quality Management and in adult patients with hepatitis B [12]. In patients of Chinese Medicinal Materials (GAP) (2002). with gastrointestinal tumors, SAOLP administration was Patients who were intolerant to SAOLP or showed associated with improved HRQoL compared to placebo SAOLP-related or chemotherapy-related toxicity or dis- [13]. This multicenter, randomized, double-blind, place- bo-controlled clinical trial was designed to evaluate the ease deterioration were transferred to the emergency safety and efficacy of SAOLP for improving HRQoL department. Patients treated for <3  weeks were only included in the safety analyses. and immune response during chemotherapy in Chinese patients with breast cancer. Outcome measures Patients’ baseline characteristics were recorded before Methods chemotherapy. The primary endpoint was the improve- Study design ment in patient HRQoL on day 42. Secondary endpoints This was a multicenter, randomized, double-blind, pla- included immunologic function (CD3, CD4, CD8), cebo-controlled, parallel-arm clinical trial. Patients were improvement in patient HRQoL on day 21 and 84, objec- randomized by the random number method to receive tive response rate (ORR), disease control rate (DCR), SAOLP or placebo, which were provided as matching BMI and adverse events. white powders with a similar taste. Patients, physicians and nurses were blinded to the treatment allocation. EORTC QLQ-C30 The official Croatian translation of the European Study participants Organisation for Research and Treatment of Cancer Patients diagnosed with breast cancer based on biopsy or (EORTC) [14] QLQ-C30 was used to assess can- histology attending the Beijing Friendship hospital affil- cer-specific HRQoL during the previous week [17]. The iated with Capital Medical University, Xiyuan Hospital, EORTC QLQ-C30 was administered on day 21, day 42 China Academy of Chinese medical sciences and Tianjin and day 84. Medical University general hospital between August 2017 and June 2019 were eligible for this study. The EORTC QLQ-C30 consists of 30 questions, includ- ing five functional scales, nine symptom scales, and a Inclusion criteria were (1) Eastern Cooperative Oncology global health status/quality of life scale (GHS/QoL). Group performance status of 0–2; (2) aged 18–75 years; Responses to 28 questions are assessed on a 4-point (3) tumor stage IV, irrespective of whether the patient Likert-type scale (‘1=‘not at all’, 2=‘a little’, 3=‘quite a had undergone surgery; (4) maximum tumor diameter bit’ and 4=‘very much’). Responses to two questions are ≥10  mm on computed tomography (CT) and MRI; (5) assessed on a 7-point scale Likert-type scale ranging from adequate hematological, hepatic and renal function; and 1=‘very poor’ to 7=‘excellent’. (6) expected overall survival of >3 months. Baseline EORTC QLQ-C30, EORTC QLQ-BR23 and Exclusion criteria were (1) participated in another clin- immune response ical trial in the past 3 months; (2) allergic to SAOLP or The EORTC QLQ-BR23 was used with the EORTC its constituents; (3) taking digitalis; or (4) psychopathic QLQ-C30 to assess breast cancer-specific HRQoL dur - tendencies, pregnant or lactating. ing the previous week, except for the sexual items, which Ethical issues were during the past 4 weeks. The EORTC QLQ-BR23 was administered on day 21, day 42 and day 84. The trial was conducted according to the Declaration of Helsinki and the Ethical Guidelines for Clinical The EORTC QLQ-BR23 consists of 23 questions, Research. The trial protocol was approved by an inde- including four functional scales and four symptom scales. pendent ethics committee at the Beijing Friendship Responses to questions are assessed on a 4-point Likert- Hospital. This trial was registered with the Chinese type scale. Clinical Trial Registry at http://www.chictr.org.cn (ChiCTR-IPR-17013733). All patients provided written Data were collected through face-to-face interviews informed consent to participate in the trial and author- and review of patients’ medical charts. Researchers ized publication of this article. collecting data were provided two days of training and Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. SAOLP Improves HRQoL for Advanced BC Wang et al. 1069 Fig. 1 Flow chart showing patient selection. Table 1 Patients’ baseline demographic and clinical characteristics Characteristics SAOLP group Control group Total statistic(χ /t) P value Age N (Nmiss) 18 (0) 18 (0) 36 (0) 3.07 0.004 Mean (SD) 60.1 (7.5) 50.7 (10.7) 55.4 (10.3) Median (Q1,Q3) 61.4 (54.2,65.1) 50.9 (43.4, 55.2) 54.3 (49.2,63.7) Min, Max 47.4, 73.7 34.6, 72.7 34.6, 73.7 BMI N (Nmiss) 18 (0) 18 (0) 36 (0) −0.53 0.598 Mean (SD) 23.5 (2.9) 24.1 (2.9) 23.8 (2.9) Median (Q1,Q3) 23.6 (20.7,24.9) 23.8 (22.6,25.0) 23.8 (22.5,25.0) Min, Max 19.4, 30.1 19.2, 31.2 19.2, 31.2 ECOG N (Nmiss) 18 (0) 18 (0) 36 (0) 0.83 0.411 Mean (SD) 0.9 (0.4) 0.8 (0.4) 09 (0.4) Median (Q1,Q3) 1.0 (1.0,1.0) 1.0 (1.0,1.0) 1.0 (1.0,1.0) Min, Max 1.0, 2.0 0.0, 1.0 0.0, 2.0 First line NO,% 16 (88.9) 12 (66.7) 28 (77.8) 1.45 0.229 YES,% 2 (11.1) 6 (33.3) (22.2) ECOG: Eastern Cooperative Oncology Group. were continuously supervised by the principal investi- Immunologic function gator. A pre-test was performed on 20 patients to pro- The number of CD3+, CD4+ and CD8+ T lymphocytes and the CD4+/CD8+ ratio were measured by flow cytom- vide feedback on the EORTC QLQ-C30 and EORTC etry to evaluate patients’ immune response. A decrease QLQ-BR23 and ensure they were applicable to the trial population. in CD3+ T lymphocytes indicates severe suppression of Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 1070 Anti-Cancer Drugs 2021, Vol 32 No 10 Table 2 Baseline EORTC QLQ-C30 scores Indicators SAOLP group control group total statistic(t) P value PF (physical function) N (Nmiss) 18 (0) 18 (0) 36 (0) 0.07 0.794 Mean (SD) 1.7 (0.3) 1.7 (0.3) 1.7 (0.3) Median (Q1,Q3) 1.7 (1.6,1.8) 1.6 (1.6,2) 1.6 (1.6,1.8) Min, Max 1.0, 2.6 1.2, 2.2 1.0, 2.6 RF (role function) N (Nmiss) 18 (0) 18 (0) 36 (0) 0.08 0.778 Mean (SD) 1.6 (0.6) 1.6 (0.6) 1.6 (0.6) Median (Q1,Q3) 1.3 (1,2) 1.5 (1.0,2.0) 1.5 (1.0,2.0) Min, Max 1.0,2.5 1.0,2.5 1.0,2.5 EF (emotional functioning) N (Nmiss) 18 (0) 18 (0) 36 (0) 0.25 0.617 Mean (SD) 1.6 (0.6) 1.7 (0.5) 1.6 (0.6) Median (Q1,Q3) 1.5 (1.0,2.3) 1.8 (1.3,2.3) 1.8 (1,2.3) Min, Max 1, 2.8 1, 2.5 1.0, 2.8 CF (cognitive function) N(Nmiss) 18(0) 18(0) 36(0) 0.15 0.702 Mean (SD) 1.5 (0.5) 1.5 (0.5) 1.5 (0.5) Median (Q1,Q3) 1.5 (1.0,2.0) 1.5 (1.0,2.0) 1.5 (1.0,2.0) Min, Max 1.0,2.5 1.0,2.5 1.0,2.5 SF (social function) N (Nmiss) 18 (0) 18 (0) 36 (0) 0.86 0.355 Mean (SD) 2.2 (0.6) 2.1 (0.5) 2.1 (0.6) Median (Q1,Q3) 2.0 (2.0,3.0) 2 (2.0,2.0) 2 (2.0,2.5) Min, Max 1,3 1,3 1,3 QL (quality) N (Nmiss) 18 (0) 18 (0) 36 (0) 2.62 0.106 Mean (SD) 3.9 (0.9) 4.3 (0.8) 4.1 (0.9) Median (Q1,Q3) 4.0 (3.0,5.0) 4.0 (4.0,5.0) 4.0 (3.3,5.0) Min, Max 2.5,5.0 3.0, 5.5 2.5, 5.5 FA (fatigue) N (Nmiss) 18 (0) 18 (0) 36 (0) Mean (SD) 1.9 (0.5) 1.8 (0.3) 1.8 (0.5) Median (Q1,Q3) 1.8 (1.3,2.0) 1.7 (1.7,2.0) 1.7 (1.7,2.0) Min, Max 1.0, 3.0 1.3, 2.3 1.0, 3.0 NV (nausea and vomiting) N (Nmiss) 18 (0) 18 (0) 36 (0) 0.41 0.52 Mean (SD) 1.2 (0.3) 1.4 (0.6) 1.3 (0.5) Median (Q1,Q3) 1.0 (1.0,1.5) 1.0 (1.0,2.0) 1.0 (1.0,1.5) Min, Max 1.0, 2.0 1.0, 3.0 1.0, 3.0 PA (pain) N (Nmiss) 18 (0) 18 (0) 36 (0) 0.92 0.339 Mean (SD) 1.9 (0.6) 1.7 (0.6) 1.8 (0.6) Median (Q1,Q3) 1.5 (1.5,2.5) 1.5 (1.0,2.0) 1.5 (1.5,2.0) Min, Max 1.0, 3.0 1.0, 3.0 1.0, 3.0 DY (dyspnea) N (Nmiss) 18 (0) 18 (0) 36 (0) 1 0.337 Mean (SD) 1.7 (0.5) 1.5 (0.5) 1.6 (0.5) Median (Q1,Q3) 2.0 (1.0,2.0) 1.5 (1.0,2.0) 2.0 (1.0,2.0) Min, Max 1.0,2.0 1.0,2.0 1.0,2.0 AP (appetite loss) N (Nmiss) 18 (0) 18 (0) 36 (0) 0.13 0.722 Mean (SD) 1.9 (0.5) 1.8 (0.5) 1.9 (0.5) Median (Q1,Q3) 2.0 (2.0,2.0) 2.0 (2.0,2.0) 2.0 (2.0,2.0) Min, Max 1.0,3.0 1.0,3.0 1.0,3.0 CO (constipation) N (Nmiss) 18 (0) 18 (0) 36 (0) 2.99 0.084 Mean (SD) 1.7 (0.5) 1.4 (0.6) 1.5 (0.6) Median (Q1,Q3) 2.0 (1.0,2.0) 1.0 (1.0,2.0) 1.5 (1.0,2.0) Min, Max 1.0,2.0 1.0,3.0 1.0,3.0 DI (diarrhea) N (Nmiss) 18 (0) 18 (0) 36 (0) 0.73 0.393 Mean (SD) 1.2 (0.4) 1.3 (0.6) 1.3 (0.5) Median (Q1,Q3) 1.0 (1.0,1.0) 1.0 (1.0,2.0) 1 (1,1) Min, Max 1.0,2.0 1.0,3.0 1.0,3.0 FI (financial difficulties) N (Nmiss) 18 (0) 18 (0) 36 (0) 3.43 0.064 Mean (SD) 2.6 (0.5) 2.2 (0.6) 2.4 (0.6) Median (Q1,Q3) 3.0 (2.0,3.0) 2.0 (2.0,3.0) 2.0 (2.0,3.0) Min, Max 2.0,3.0 1.0,3.0 1.0,3.0 cellular immune function. CD4 and CD8 are two impor- partial response. DCR was defined as the percentage of tant T lymphocyte subsets. A decrease in CD4+ T lym- patients who had a complete response, partial response, phocytes indicates a decrease in lymphocyte function and and stable disease. B cell antibody production. A decrease in the CD4+/CD8+ ratio reflects a reduction in the health of the immune Adverse events system. Adverse events were reported based on the Common Terminology Criteria for Adverse Events, version 4.0. Evaluation of tumor response CT was performed 4  weeks before study initiation and Statistical analysis 9 weeks after the end of treatment to evaluate tumor size Sample size was determined according to previous obser- and status. Response rates were assessed by investiga- vations using the same primary outcome measure. Fifteen tors according to Response Evaluation Criteria in Solid participants per arm were required to detect a treatment Tumors (RECIST, version 1.1). ORR was defined as the effect with 80% power and a two-sided significance level percentage of patients who had a complete response and of 5% on the physical functioning score on the EORTC Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. SAOLP Improves HRQoL for Advanced BC Wang et al. 1071 Table 3 Baseline EORTC QLQ-BR23 scores Indicators SAOLP group Control group Total Statistic(t) P value BRBI (body image) N (Nmiss) 18 (0) 18 (0) 36 (0) 0.19 0.666 Mean (SD) 1.9 (0.6) 2 (0.5) 1.9 (0.5) Median (Q1,Q3) 1 (3.3,0) 1 (3,0) 2 (1.6,2) Min, Max 1, 3.3 1, 3 1,3.3 BRSFF (sexual functioning) N (Nmiss) 18 (0) 18 (0) 36 (0) 0.98 0.323 Mean (SD) 1.6 (0.5) 1.4 (0.5) 1.5 (0.5) Median (Q1,Q3) 1 (2,0) 1 (2,0) 1 (1,2) Min, Max 1, 2 1, 2 1, 2 BRSEE (sexual enjoyment) N (Nmiss) 11 (7) 8 (10) 36 (0) 0.73 0.394 Mean (SD) 1.9 (0.3) 2 (0) 1.9 (0.2) Median (Q1,Q3) 1 (2,0) 2 (2,0) 2 (2,2) Min, Max 1,2 2, 2 1, 2 BRFU (future perspective) N (Nmiss) 18 (0) 18 (0) 36 (0) 0.03 0.871 Mean (SD) 2.5 (0.6) 2.5 (0.5) 2.5 (0.6) Median (Q1,Q3) 2 (4,0) 2 (3,0) 2 (2,3) Min, Max 2,4 2,3 2,4 BRST (systemic therapy side effects) N (Nmiss) 18 (0) 18 (0) 36 (0) 0.41 0.521 Mean (SD) 1.6 (0.3) 1.5 (0.3) 1.6 (0.3) Median (Q1,Q3) 1.1 (2.3,0) 1 (2.1,0) 1.5 (1.3,1.9) Min, Max 1.1, 2.3 1, 2.1 1, 2.3 BRBS (breast symptoms) N (Nmiss) 18 (0) 18 (0) 36 (0) 0.19 0.662 Mean (SD) 1.6 (0.4) 1.6(0.4) 1.6 (0.4) Median (Q1,Q3) 1 (2,0) 1 (2.3,0) 1.6 (1.3,2) Min, Max 1, 2 1, 2.3 1, 2.3 BRAS (arm symptoms) N (Nmiss) 11 (7) 9 (9) 20 (16) 0.2 0.657 Mean (SD) 1.6 (0.4) 1.6 (0.4) 1.6 (0.4) Median (Q1,Q3) 1 (2.7,0) 1 (2.3,0) 1.7 (1.3,2) Min, Max 1, 2.7 1, 2.3 1, 2.7 BRHL (upset by hair loss) N (Nmiss) 14 (4) 11(7) 27 (9) 0.14 0.705 Mean (SD) 2 (0.6) 1.9 (0.5) 2 (0.5) Median (Q1,Q3) 1 (3,0) 1(3,0) 2 (2,2) Min, Max 1, 3 1, 3 1, 3 Table 4 Baseline immune response Indicators SAOLP Placebo Total Statistic(t) P value CD3 N (Nmiss) 18 (0) 18 (0) 36(0) 0.53 0.597 Mean (SD) 68.6 (10.4) 66.9 (9.5) 67.8 (9.9) Median (Q1,Q3) 66.6 (59.4,76.3) 63.8 (59.4,77.2) 65.5 (59.4,76.7) Min, Max 57.6, 89.7 54.4, 84.3 54.4, 89.7 CD4 N (Nmiss) 18 (0) 18 (0) 36 (0) 1.19 0.244 Mean (SD) 37.3 (8.3) 34.5 (5.7) 35.9 (7.2) Median (Q1,Q3) 34.4 (32.4,43.6) 34.4 (30.2,39.6) 34.4 (30.7,39.8) Min, Max 28.7, 63.0 26.9, 44.2 26.9, 63.0 CD8 N (Nmiss) 18 (0) 18 (0) 36(0) −1.49 0.145 Mean (SD) 25.4 (9.9) 29.8 (8.0) 27.6 (9.1) Median (Q1,Q3) 24.2 (20.1,28.9) 29.8 (22.3,36.5) 26.1 (20.3,35.8) Min, Max 10.9, 50.5 18.4, 43.6 10.9 (50.5) QLQ-C30 and EORTC QLQ-BR23. Accounting for a chemotherapy and SAOLP or placebo were compared 15% withdrawal and dropout rate, 36 subjects, 18 per arm, with the two-sample independent t test. Statistical were needed to ensure statistically significant results. analyses were performed with SPSS v20.0 (IBM SPSS Inc., Chicago, Illinois, USA) using a two-sided analysis. Continuous data are reported as mean, SD, median, mini- P < 0.05 was considered statistically significant. mum and maximum. Categorical variables are reported as number of cases and percentage. Standardized EORTC Results QLQ-C30 and EORTC QLQ-BR23 scores were calcu- Patient characteristics lated according to the following formulae: (1) for func- This study included 36 patients with breast cancer diag- tional items, standardized score=[1  −  (crude score−1)/ nosed based on biopsy or histology. All patients had stage range] × 100; 2) for general health and symptomatic items, IV ductal adenocarcinoma of the breast. Thirty patients standardized score=[(crude score  −  1)  ×  range]  ×  100. underwent surgery, 28 patients received preoperative Thus, for functional and general health items, a higher first-line chemotherapy, 16 patients received endocrine standardized score indicated better patient HRQoL. In treatment and 10 patients received radiotherapy. contrast, for symptomatic items, a higher standardized score indicated worse patient HRQoL. Standardized Eighteen patients each were randomized to receive EORTC QLQ-C30 and EORTC QLQ- BR23 scores SAOLP or placebo. Four patients were lost to follow-up on day 21, day 42 and day 84 for patients treated with and did not have data relevant to the primary outcome Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 1072 Anti-Cancer Drugs 2021, Vol 32 No 10 Table 5 EORTC QLQ-C30 scores on day 21, day 48 and day 84 Indicators Placebo SAOLP Statistic(t) P value Placebo SAOLP Statistic(t) P value Placebo SAOLP Statistic(t) P value (day 21) (day 21) (day 21) (day 42) (day 42) (day 42) (day 84) (day 84) (day84) (day 21) (day 42) (day 84) PF (physical function) N (Nmiss) 17 (1) 17 (1) 1.21 0.235 17 (1) 15 (3) 6.95 <0.001 17 (1) 15 (3) 7.75 <0.001 Mean (SE) 78.4(2.0) 74.9(2.1) 83.1(2.1) 58.7(2.9) 84.7(1.9) 57.3(3.1) RF (role function) N (Nmiss) 17 (1) 17 (1) 1.6 0.119 17 (1) 15 (3) 4.12 <0.001 17 (1) 15 (3) 8.36 <0.001 Mean (SE) 82.4 (5.0) 71.6 (4.5) 87.3 (4.2) 58.9 (5.6) 90.2 (3.5) 48.9 (7.0) EF (emotional functioning) N (Nmiss) 17 (1) 17 (1) 0.93 0.362 17 (1) 15 (3) 6.47 <0.001 17 (1) 15 (3) 6.76 <0.001 Mean (SE) 82.4 (4.1) 76.5 (4.9) 93.6 (2.4) 60.6 (4.7) 94.6 (2.1) 60.0 (4.9) CF (cognitive function) N (Nmiss) 17 (1) 17 (1) 1.94 0.061 17 (1) 15 (3) 2.94 0.006 17 (1) 15 (3) 6.19 <0.001 Mean (SE) 83.3 (3.2) 74.5 (3.2) 92.2 (3.2) 76.7 (4.2) 92.2 (2.9) 63.3 (3.7) SF (social function) N (Nmiss) 17(1) 17 (1) 1.71 0.096 17 (1) 15 (3) 5.6 <0.001 17 (1) 15 (3) 6.42 <0.001 Mean (SE) 68.6 (4.7) 58.8 (3.2) 79.4 (3.7) 46.7 (4.7) 80.4 (3.6) 40.0 (5.3) QL (quality) N (Nmiss) 17 (1) 17 (1) 2.56 0.015 17 (1) 15 (3) 10.53 <0.001 17 (1) 15 (3) 13.59 <0.001 Mean (SE) 60.8 (2.7) 50.0 (3.2) 78.9 (2.4) 37.2 (3.2) 81.4 (1.5) 32.8 (3.4) FA (fatigue) N (Nmiss) 17 (1) 17 (1) −1.21 0.233 17 (1) 15 (3) −6.72 <0.001 17 (1) 15 (3) −8.52 <0.001 Mean (SE) 26.1 (3.9) 32.0 (2.8) 13.1 (3.0) 51.1 (4.9) 9.8 (2.3) 62.2 (6.0) NV (nausea and vomiting) N (Nmiss) 17 (1) 17 (1) −1.37 0.18 17 (1) 15 (3) −1.92 0.0 64 17 (1) 15 (3) −2.47 0.019 Mean (SE) 6.9 (2.9) 13.7 (4.1) 4.9 (2.8) 15.6 (5.0) 4.9 (2.4) 16.7 (4.3) PA (pain) N (Nmiss) 17 (1) 17 (1) −0.32 0.754 17 (1) 15 (3) −2.3 0.029 17 (1) 15 (3) −3.39 0.002 Mean(SE) 21.6(4.7) 23.5(4.1) 14.7(3.7) 30.0(5.7) 11.8(4.0) 34.4(5.5) DY (dyspnea) N (Nmiss) 17 (1) 17 (1) −0.68 0.28 17 (1) 15 (3) −2.67 0.012 17 (1) 15 (3) −3.68 0.001 Mean (SE) 17.6 (4.2) 21.6 (4.0) 9.8 (3.8) 24.4 (3.9) 5.9 (4.3) 26.7 (3.6) AP (appetite loss) N (Nmiss) 17 (1) 17 (1) −0.65 0.518 17 (1) 15 (3) −2.91 0.007 17 (1) 15 (3) −2.23 0.033 Mean (SE) 25.5 (4.5) 29.4 (3.9) 13.7 (4.1) 28.9 (3.0) 19.6 (4.1) 33.3 (4.6) CO (constipation) N (Nmiss) 17 (1) 17 (1) 0.34 0.734 17 (1) 15 (3) −1.4 0.171 17 (1) 15 (3) −2.3 0.029 Mean (SE) 13.7 (4.1) 17.8 (4.0) 5.9 (3.2) 13.3 (4.4) 3.9 (2.7) 15.6 (4.4) DI (diarrhea) N (Nmiss) 17 (1) 17 (1) −0.79 0.434 17 (1) 15 (3) −2.05 0.049 17 (1) 15 (3) −2.61 0.014 Mean (SE) 5.9 (3.2) 9.8 (3.8) 2.0 (2.0) 11.1 (4.2) 0 (0) 13.3 (5.4) FI (financial difficulties) N (Nmiss) 17 (1) 17 (1) 0.3 0.765 17 (1) 15 (3) −2.06 0.048 17 (1) 15 (3) −4.67 <0.001 Mean (SE) 49.0 (4.2) 47.1 (5.0) 41.2 (3.5) 57.8 (7.6) 35.3 (4.5) 71.1 (6.4) Table 6 EORTC QLQ-BR23 scores on day 21, day 48 and day 84 Indicators SAOLP Placebo Statistic(t) SAOLP Placebo Statistic(t) SAOLP Placebo Statistic(t) P value P value P value (day 21) (day 21) (day 21) (day 21) (day 42) (day 42) (day 42) (day 42) (day 84) (day 84) (day84) (day 84) BRBI (body image) N (Nmiss) 17 (1) 17 (1) 2.1 0.044 17 (1) 15 (3) 6.98 <0.001 17 (1) 15 (3) 7.08 <0.001 Mean (SE) 77.9 (4.3) 64.2 (4.9) 83.8 (4.0) 45.0 (3.8) 85.8 (3.3) 46.7 (4.6) BRSFF (sexual functioning) N (Nmiss) 17 (1) 17 (1) −1.02 0.315 17 (1) 15 (3) −1.37 0.181 17 (1) 15 (3) −1.37 0.181 Mean (SE) 82.4 (4.2) 88.2 (4.0) 83.3 (4.0) 91.1 (3.9) 83.3 (4.0) 91.1 (3.9) BRSEE (sexual enjoyment) N (Nmiss) 10 (8) 6 (12) 0.76 0.458 10 (8) 10 (8) −1.9 0.074 11 (7) 10 (8) −1.53 0.144 Mean (SE) 70.0 (3.3) 66.7 (0) 73.3 (4.4) 86.7 (5.4) 75.8 (4.7) 86.7 (5.4) BRFU (future perspective) N (Nmiss) 17 (1) 17 (1) 2.58 0.015 17 (1) 15 (3) 4.36 <0.001 17 (1) 15 (3) 6.14 <0.001 Mean (SE) 58.8 (3.5) 45.1 (4.0) 66.7 (5.0) 35.6 (5.1) 68.6 (4.5) 22.2 (6.2) BRST (systemic therapy N (Nmiss) 17 (1) 17 (1) −0.47 0.641 17 (1) 15 (3) −2.92 0.007 17 (1) 15 (3) −4 <0.001 side effects) Mean (SE) 18.2 (2.3) 19.9 (2.7) 12.6 (3.0) 25.1 (3.0) 11.5 (2.3) 26.7 (3.0) BRBS (breast symptoms) N (Nmiss) 17 (1) 17 (1) −0.42 0.675 16 (2) 15 (3) −4.07 <0.001 17 (1) 15 (3) −5.21 <0.001 Mean (SE) 19.6 (2.7) 21.6 (3.8) 12.0 (2.7) 30.6 (3.7) 8.3 (2.3) 30.0 (3.6) BRAS (arm symptoms) N (Nmiss) 17 (1) 17 (1) −0.68 0.502 17 (1) 15 (3) −1.98 0.0 57 17 (1) 15 (3) −2.72 0.011 Mean (SE) 17.6 (2.7) 20.3 (2.7) 15.7 (2.5) 23.7 (3.2) 14.4 (2.3) 25.2 (3.3) BRHL (upset by hair loss) N (Nmiss) 12 (6) 12 (6) −0.69 0.496 8 (10) 10 (8) −1.56 0.138 11 (7) 11 (7) −1.78 0.091 Mean (SE) 33.3 (7.1) 38.9 (3.7) 29.2 (11.7) 50.0 (7.5) 24.2 (9.1) 42.4 (4.7) measure; therefore, data from 32 patients were included EORTC QLQ-C30 on day 21, day 42 and day 84 On day 21, the score on the global health status/QoL in the final analysis (Fig. 1). scale was significantly higher in patients who received The demographic and baseline characteristics of the SAOLP compared to placebo. There were no signif- included patients are summarized in Table  1. Patients icant differences in scores on the functional scales had a median age of 55.4 years (range 49.2–63.7). 22.2% or the symptom scales. On day 42, scores on the five of patients received first-line chemotherapy, and 77.8% functional scales (physical, role, cognitive, emotional of patients received second- or later-line chemotherapy. and social) and the global health status/QoL scale were significantly higher in patients who received EORTC QLQ-BR23 SAOLP compared to placebo (P < 0.05). Scores on six There were no significant differences in baseline EORTC of the symptom scales (fatigue, pain, dyspnea, loss of QLQ-C30 (Table  2), EORTC QLQ-BR23 (Table  3) or appetite, diarrhea and financial difficulties) were sig- immune response in patients who received SAOLP or nificantly lower in patients who received SAOLP com- placebo (Table 4). pared to placebo (P  <  0.05). On day 84, scores on the Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. SAOLP Improves HRQoL for Advanced BC Wang et al. 1073 Table 7 Immune response on day 21, day 48, and day 84 Indicators SAOLP (day 21) Placebo (day 21) Statistic(t) P value CD3 N (Nmiss) 17 (1) 17 (1) 1.86 0.073 Mean (SE) 70.5 (2.3) 64.4 (2.4) CD4 N (Nmiss) 17 (1) 17 (1) 2.05 0.049 Mean (SE) 36.7 (1.4) 32.9 (1.1) CD8 N (Nmiss) 17 (1) 17 (1) 1.25 0.219 Mean (SE) 30.1 (2.6) 25.9 (2.1) CD4/CD8 N (Nmiss) 17 (1) 17 (1) 0.15 0.879 Mean (SE) 1.38 (0.14) 1.36 (0.08) Indicators SAOLP (day 42) Placebo (day 42) Statistic(t) P value CD3 N (Nmiss) 17 (1) 14 (3) 10.47 <0.001 Mean (SE) 76.1 (1.4) 59.0 (5.0) CD4 N (Nmiss) 17 (1) 14 (3) 6.12 <0.001 Mean (SE) 39.2 (1.4) 29.0 (0.6) CD8 N (Nmiss) 17 (1) 14 (3) 5.52 <0.001 Mean (SE) 34.6 (2.3) 20.5 (0.6) CD4/CD8 N (Nmiss) 17 (1) 14 (3) −2.02 0.055 Mean (SE) 1.22 (0.09) 1.43 (0.04) Indicators SAOLP (day 84) Placebo (day 84) Statistic(t) P value CD3 N (Nmiss) 17 (1) 14 (4) 15.1 <0.001 Mean (SE) 77.8 (1.2) 57.7 (0.4) CD4 N (Nmiss) 17 (1) 14 (4) 5.31 <0.001 Mean (SE) 42.0 (1.5) 29.0 (2.2) CD8 N (Nmiss) 17 (1) 14 (4) 8.82 <0.001 Mean (SE) 36.9 (1.8) 18.9 (0.3) CD4/CD8 N (Nmiss) 17 (1) 14 (4) −2.58 0.015 Mean (SE) 1.20 (0.07) 1.53 (0.11) Table 8 BMI on day 21, day 48 and day 84 Immune response on day 21, day 42 and day 84 On day 21, there were no significant differences in the Indicators SAOLP Placebo Statistic(t) P value number of CD3, CD4 or CD8 cells or the CD4/CD8 BMI_Day 21 N (Nmiss) 17 (1) 17 (1) 0.06 0.951 ratio in patients who received SAOLP or placebo. On Mean (SE) 23.7 (0.7) 23.6 (0.7) day 42, the number of CD3, CD4 and CD8 cells were BMI_Day 42 N (Nmiss) 17 (1) 15 (3) 0.2 0.84 Mean (SE) 23.4 (0.8) 23.2 (0.7) significantly higher in patients who received SAOLP BMI_Day 84 N (Nmiss) 17 (1) 15 (3) 1.49 0.147 compared to placebo (P  <  0.05). On day 84, the num- Mean (SE) 23.6 (0.7) 22.2 (0.5) ber of CD3, CD4 and CD8 cells and the CD4/CD8 ratio were significantly higher in patients who received five functional scales (physical, role, cognitive, emo- SAOLP compared to placebo (P < 0.05) (Table 7). tional and social) and the global health status/QoL scale were significantly higher in patients who received Objective effective rate and disease control rate SAOLP compared to placebo (P < 0.05). Scores on the ORR was 7.1% and 8.3% (P  =  1.000) in patients who nine symptom scales (fatigue, pain, nausea and vomit- received SAOLP or placebo, respectively. DCR was 100 ing, dyspnea, loss of appetite, insomnia, constipation, and 83.3% (P = 0.203) in patients who received SAOLP diarrhea and financial difficulties) were significantly or placebo, respectively. There were no significant differ - lower in patients who received SAOLP compared to ences in ORR or DCR in patients who received SAOLP placebo (Table 5). or placebo (Table 8). EORTC QLQ-BR23 on day 21, day 42 and day 84 BMI On day 21, scores on two of the functional scales (body On day 21, day 42 and day 84, BMI was higher in patients image and future perspective) were significantly higher who received SAOLP compared to placebo, but the dif- in patients who received SAOLP compared to placebo ferences were NS. (P  <  0.05). On day 42, scores on two of the functional scales (body image and future perspective) were signif- Safety icantly higher and scores on two of the symptom scales Across all enrolled patients, 47.22% (17/36) of patients (systemic therapy side effects and breast symptoms) were reported an adverse event. Most of the adverse events significantly lower in patients who received SAOLP com- were Grade 1 or 2. Frequent nonhematological toxici- pared to placebo (P < 0.05). On day 84, scores on two of ties included nausea/vomiting, fatigue and proteinuria. the functional scales (body image and future perspec- Among patients who received SAOLP, 50% (9/18) of tive) were significantly higher and scores on three of the patients reported an adverse event. Among patients who symptom scales (systemic therapy side effects, breast received placebo, 44.4% (8/18) of patients reported an symptoms and arm symptoms) were significantly lower adverse event. No patients reported a serious drug-re- in patients who received SAOLP compared to placebo lated adverse event. All adverse events were considered (P < 0.05) (Table 6). related to chemotherapy. Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 1074 Anti-Cancer Drugs 2021, Vol 32 No 10 cancer. SAOLP represents a convenient and safe adju- Discussion vant therapy. This clinical trial was designed to evaluate the safety and efficacy of SAOLP for improving HRQoL and immune Acknowledgements response during chemotherapy in Chinese patients with This study was supported by grants from Beijing Key breast cancer. Breast cancer treatment involves a mul- Specialty (Bangwei Cao). timodal approach that includes chemotherapy [15]. Chemotherapy can significantly improve survival and qual- ity of life compared to best supportive care in patients with All authors contributed to the study’s conception and design. Material preparation, data collection and analy- breast cancer [16–18]. However, adverse effects of chemo- sis were performed by J.W., X.M., K.S., S.W., Y.M., Z.M. therapy in patients with malignant tumors include fatigue, and B.C. The first draft of the manuscript was written by nausea and vomiting, bone marrow suppression, renal J.W., and all authors commented on previous versions of toxicity, neurotoxicity and cancer-related cognitive impair- the manuscript. All authors read and approved the final ment [19]. Accordingly, most patients with breast cancer manuscript. experience a decline in HRQoL due to tumor burden and treatment effects, such as loss of appetite, reduction in Conflicts of interest body mass and emotional instability. Improving the quality There are no conflicts of interest. of life of patients with cancer is essential to decrease psy- chological distress and enhance coping [20,21]. Disease, such as malignant tumor, may weaken the immune sys- References 1 Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin tem, which can have a direct effect on treatment outcomes 2020; 70:7–30. and prognosis. Therapies that manipulate the immune 2 Miller KD, Nogueira L, Mariotto AB, Rowland JH, Yabroff KR, Alfano CM, et system may achieve long-term cancer regression. al. Cancer treatment and survivorship statistics, 2019. CA Cancer J Clin 2019; 69:363–385. 3 DeSantis CE, Ma J, Gaudet MM, Newman LA, Miller KD, Goding SAOLP consists of polypeptides and nucleotides Sauer A, et al. Breast cancer statistics, 2019. CA Cancer J Clin 2019; extracted from the pig spleen, which may enhance the 69:438–451. 4 Sitlinger A, Zafar SY. Health-related quality of life: the impact on morbidity body’s cellular immunity, stimulate the release of a vari- and mortality. 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Costs and effectiveness of mindfulness-based art therapy versus HRQoL and immune response in patients with advanced Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. SAOLP Improves HRQoL for Advanced BC Wang et al. 1075 standard breast cancer support group for women with cancer. Am Health for physical therapy: systematic review of randomized controlled trials. Phys Drug Benefits 2017; 10 :288–295. Ther 2020; 100:523–542. 17 Freedman RA, Partridge AH. Emerging data and current challenges for 20 Konieczny M, Cipora E, Sygit K, Fal A. Quality of life of women with breast young, old, obese, or male patients with breast cancer. Clin Cancer Res cancer and socio-demographic factors. Asian Pac J Cancer Prev 2020; 2017; 23:2647–2654. 21:185–193. 18 Haussmann J, Nestle-Kraemling C, Bölke E, Wollandt S, Speer V, 21 Mojgan F, Karimollah HT, Moslemi D. Analysis of quality of life in breast Djiepmo Njanang FJ, et al. 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Safety and efficacy of spleen aminopeptide oral lyophilized powder for improving quality of life and immune response in patients with advanced breast cancer: a multicenter, randomized, double-blind, placebo-controlled clinical trial

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Abstract

Original article 1067 Safety and efficacy of spleen aminopeptide oral lyophilized powder for improving quality of life and immune response in patients with advanced breast cancer: a multicenter, randomized, double-blind, placebo-controlled clinical trial Jing Wang, Xiao Ma, Kun Shang, Shanshan Wu, Yan Ma, Zhongjun Ma and Bangwei Cao Health-related quality of life (HRQoL) is an important On day 84, the number of CD3, CD4 and CD8 cells were consideration in managing patients. Spleen significantly higher in patients who received SAOLP. aminopeptide oral lyophilized powder (SAOLP) has There were no significant differences in objective been used to enhance cellular immunity in a patient. response rate, disease control rate or BMI. SAOLP may This multicenter, randomized, double-blind, placebo- improve HRQoL and the immune response in patients controlled clinical trial was designed to evaluate the with advanced breast cancer, represents a convenient safety and efficacy of SAOLP for improving HRQoL and safe adjuvant therapy. Anti-Cancer Drugs 32: in patients with breast cancer. Patients diagnosed 1067–1075 Copyright © 2021 The Author(s). Published with advanced breast cancer were included, and were by Wolters Kluwer Health, Inc. administered SAOLP or placebo 4 mg qd for two cycles. Anti-Cancer Drugs 2021, 32:1067–1075 The primary endpoint was improvement in HRQoL on Keywords: breast cancer, clinical trial, immune response, quality of life, day 42 measured by the EORTC QLQ-C30 and EORTC spleen aminopeptide oral lyophilized powder QLQ-BR23. Secondary endpoints included immunologic Department of Oncology, Beijing Friendship Hospital, Capital Medical University, function, improvement in HRQoL on day 21 and 84, Beijing, China objective response rate, disease control rate, BMI and Correspondence to Bangwei Cao, PhD, Department of Oncology, Beijing adverse events. On day 42, on the EORTC QLQ-C30 Friendship Hospital, Capital Medical University, #95 Yong An Road, Xicheng or EORTC QLQ-BR23, scores on the functional scales District, Beijing 100050, China Tel: +86 010 63139321; fax: +86 010 63139321; and QoL scale were significantly higher and scores on e-mail: oncology@ccmu.edu.cn symptom scales were significantly lower in patients Received 31 March 2021 Revised form accepted 30 May 2021 who received SAOLP compared to placebo (P < 0.05). Introduction (92%) and breast cancer (women) (90%) [1] During In the United States (US), in 2020, there will be 2012–2016, the incidence of breast cancer in the US approximately 1  806  590 new cancer diagnoses and increased 0.3% per year, driven by an increased inci- 606 520 cancer-related deaths [1]. On 1 January 2030, dence of local stage and hormone receptor-positive an estimated 22.1 million Americans will be living disease [3]. with a cancer history, an increase from the 16.9 million Treatment for breast cancer includes surgery, radio- Americans who were living with a cancer history on 1 therapy and cytotoxic and endocrine drugs. Clinically, January 2019. In the US, in 2019, the most prevalent the goal of breast cancer treatment is to remove all vis- cancers among males included prostate (3  650  030), ible cancer and manage the disease over the long term. colon and rectum (776  120), and melanoma of the Patient health-related quality of life (HRQoL), defined skin (684 470), and the most prevalent cancers among as the patient-perceived psychosocial, emotional females included breast (3  861  520), uterine corpus and physical outcomes of medical intervention [4], is (807  860), and colon and rectum (768  650). Among another important aspect of breast cancer treatment cancer survivors in the US in 2019, 56% received their [5,6]. In particular, patient HRQoL should be consid- diagnosis during the last decade, and 64% were aged ered when a treatment approach is unlikely to improve ≥65 years [2]. Across all stages, survival rates were high- survival, as in some metastatic cancers. The American est for prostate cancer (98%), melanoma of the skin Society of Clinical Oncology, National Institutes of This is an open-access article distributed under the terms of the Creative Health and the National Cancer Institute recommend Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY- that patients should only be exposed to treatments NC-ND), where it is permissible to download and share the work provided it is LWW without evidence of survival benefits if they can reason- properly cited. The work cannot be changed in any way or used commercially without permission from the journal. ably expect an improvement in HRQoL. Accordingly, 0959-4973 Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. DOI: 10.1097/CAD.0000000000001109 Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 1068 Anti-Cancer Drugs 2021, Vol 32 No 10 HRQoL evaluation is increasingly recognized as an Treatment important outcome measure in clinical trials [7]. Breast cancer patients received standard therapy recom- mended by the NCCN Clinical Practice Guidelines in Spleen aminopeptide oral lyophilized powder (SAOLP), Oncology: Breast Cancer. Patients were administered which consists of peptides and nucleotides extracted from SAOLP or placebo (Fu Ketuo, Zhejiang Feng; State fresh pig spleen [8], has been used to enhance cellular Medical Permit No. H20068132) 4 mg qd po. on the first immunity and immune homeostasis in pediatric patients day of chemotherapy for two cycles. SAOLP was manufac- with respiratory infection [9] or immune disorders [10,11], tured according to the Standard for Quality Management and in adult patients with hepatitis B [12]. In patients of Chinese Medicinal Materials (GAP) (2002). with gastrointestinal tumors, SAOLP administration was Patients who were intolerant to SAOLP or showed associated with improved HRQoL compared to placebo SAOLP-related or chemotherapy-related toxicity or dis- [13]. This multicenter, randomized, double-blind, place- bo-controlled clinical trial was designed to evaluate the ease deterioration were transferred to the emergency safety and efficacy of SAOLP for improving HRQoL department. Patients treated for <3  weeks were only included in the safety analyses. and immune response during chemotherapy in Chinese patients with breast cancer. Outcome measures Patients’ baseline characteristics were recorded before Methods chemotherapy. The primary endpoint was the improve- Study design ment in patient HRQoL on day 42. Secondary endpoints This was a multicenter, randomized, double-blind, pla- included immunologic function (CD3, CD4, CD8), cebo-controlled, parallel-arm clinical trial. Patients were improvement in patient HRQoL on day 21 and 84, objec- randomized by the random number method to receive tive response rate (ORR), disease control rate (DCR), SAOLP or placebo, which were provided as matching BMI and adverse events. white powders with a similar taste. Patients, physicians and nurses were blinded to the treatment allocation. EORTC QLQ-C30 The official Croatian translation of the European Study participants Organisation for Research and Treatment of Cancer Patients diagnosed with breast cancer based on biopsy or (EORTC) [14] QLQ-C30 was used to assess can- histology attending the Beijing Friendship hospital affil- cer-specific HRQoL during the previous week [17]. The iated with Capital Medical University, Xiyuan Hospital, EORTC QLQ-C30 was administered on day 21, day 42 China Academy of Chinese medical sciences and Tianjin and day 84. Medical University general hospital between August 2017 and June 2019 were eligible for this study. The EORTC QLQ-C30 consists of 30 questions, includ- ing five functional scales, nine symptom scales, and a Inclusion criteria were (1) Eastern Cooperative Oncology global health status/quality of life scale (GHS/QoL). Group performance status of 0–2; (2) aged 18–75 years; Responses to 28 questions are assessed on a 4-point (3) tumor stage IV, irrespective of whether the patient Likert-type scale (‘1=‘not at all’, 2=‘a little’, 3=‘quite a had undergone surgery; (4) maximum tumor diameter bit’ and 4=‘very much’). Responses to two questions are ≥10  mm on computed tomography (CT) and MRI; (5) assessed on a 7-point scale Likert-type scale ranging from adequate hematological, hepatic and renal function; and 1=‘very poor’ to 7=‘excellent’. (6) expected overall survival of >3 months. Baseline EORTC QLQ-C30, EORTC QLQ-BR23 and Exclusion criteria were (1) participated in another clin- immune response ical trial in the past 3 months; (2) allergic to SAOLP or The EORTC QLQ-BR23 was used with the EORTC its constituents; (3) taking digitalis; or (4) psychopathic QLQ-C30 to assess breast cancer-specific HRQoL dur - tendencies, pregnant or lactating. ing the previous week, except for the sexual items, which Ethical issues were during the past 4 weeks. The EORTC QLQ-BR23 was administered on day 21, day 42 and day 84. The trial was conducted according to the Declaration of Helsinki and the Ethical Guidelines for Clinical The EORTC QLQ-BR23 consists of 23 questions, Research. The trial protocol was approved by an inde- including four functional scales and four symptom scales. pendent ethics committee at the Beijing Friendship Responses to questions are assessed on a 4-point Likert- Hospital. This trial was registered with the Chinese type scale. Clinical Trial Registry at http://www.chictr.org.cn (ChiCTR-IPR-17013733). All patients provided written Data were collected through face-to-face interviews informed consent to participate in the trial and author- and review of patients’ medical charts. Researchers ized publication of this article. collecting data were provided two days of training and Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. SAOLP Improves HRQoL for Advanced BC Wang et al. 1069 Fig. 1 Flow chart showing patient selection. Table 1 Patients’ baseline demographic and clinical characteristics Characteristics SAOLP group Control group Total statistic(χ /t) P value Age N (Nmiss) 18 (0) 18 (0) 36 (0) 3.07 0.004 Mean (SD) 60.1 (7.5) 50.7 (10.7) 55.4 (10.3) Median (Q1,Q3) 61.4 (54.2,65.1) 50.9 (43.4, 55.2) 54.3 (49.2,63.7) Min, Max 47.4, 73.7 34.6, 72.7 34.6, 73.7 BMI N (Nmiss) 18 (0) 18 (0) 36 (0) −0.53 0.598 Mean (SD) 23.5 (2.9) 24.1 (2.9) 23.8 (2.9) Median (Q1,Q3) 23.6 (20.7,24.9) 23.8 (22.6,25.0) 23.8 (22.5,25.0) Min, Max 19.4, 30.1 19.2, 31.2 19.2, 31.2 ECOG N (Nmiss) 18 (0) 18 (0) 36 (0) 0.83 0.411 Mean (SD) 0.9 (0.4) 0.8 (0.4) 09 (0.4) Median (Q1,Q3) 1.0 (1.0,1.0) 1.0 (1.0,1.0) 1.0 (1.0,1.0) Min, Max 1.0, 2.0 0.0, 1.0 0.0, 2.0 First line NO,% 16 (88.9) 12 (66.7) 28 (77.8) 1.45 0.229 YES,% 2 (11.1) 6 (33.3) (22.2) ECOG: Eastern Cooperative Oncology Group. were continuously supervised by the principal investi- Immunologic function gator. A pre-test was performed on 20 patients to pro- The number of CD3+, CD4+ and CD8+ T lymphocytes and the CD4+/CD8+ ratio were measured by flow cytom- vide feedback on the EORTC QLQ-C30 and EORTC etry to evaluate patients’ immune response. A decrease QLQ-BR23 and ensure they were applicable to the trial population. in CD3+ T lymphocytes indicates severe suppression of Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 1070 Anti-Cancer Drugs 2021, Vol 32 No 10 Table 2 Baseline EORTC QLQ-C30 scores Indicators SAOLP group control group total statistic(t) P value PF (physical function) N (Nmiss) 18 (0) 18 (0) 36 (0) 0.07 0.794 Mean (SD) 1.7 (0.3) 1.7 (0.3) 1.7 (0.3) Median (Q1,Q3) 1.7 (1.6,1.8) 1.6 (1.6,2) 1.6 (1.6,1.8) Min, Max 1.0, 2.6 1.2, 2.2 1.0, 2.6 RF (role function) N (Nmiss) 18 (0) 18 (0) 36 (0) 0.08 0.778 Mean (SD) 1.6 (0.6) 1.6 (0.6) 1.6 (0.6) Median (Q1,Q3) 1.3 (1,2) 1.5 (1.0,2.0) 1.5 (1.0,2.0) Min, Max 1.0,2.5 1.0,2.5 1.0,2.5 EF (emotional functioning) N (Nmiss) 18 (0) 18 (0) 36 (0) 0.25 0.617 Mean (SD) 1.6 (0.6) 1.7 (0.5) 1.6 (0.6) Median (Q1,Q3) 1.5 (1.0,2.3) 1.8 (1.3,2.3) 1.8 (1,2.3) Min, Max 1, 2.8 1, 2.5 1.0, 2.8 CF (cognitive function) N(Nmiss) 18(0) 18(0) 36(0) 0.15 0.702 Mean (SD) 1.5 (0.5) 1.5 (0.5) 1.5 (0.5) Median (Q1,Q3) 1.5 (1.0,2.0) 1.5 (1.0,2.0) 1.5 (1.0,2.0) Min, Max 1.0,2.5 1.0,2.5 1.0,2.5 SF (social function) N (Nmiss) 18 (0) 18 (0) 36 (0) 0.86 0.355 Mean (SD) 2.2 (0.6) 2.1 (0.5) 2.1 (0.6) Median (Q1,Q3) 2.0 (2.0,3.0) 2 (2.0,2.0) 2 (2.0,2.5) Min, Max 1,3 1,3 1,3 QL (quality) N (Nmiss) 18 (0) 18 (0) 36 (0) 2.62 0.106 Mean (SD) 3.9 (0.9) 4.3 (0.8) 4.1 (0.9) Median (Q1,Q3) 4.0 (3.0,5.0) 4.0 (4.0,5.0) 4.0 (3.3,5.0) Min, Max 2.5,5.0 3.0, 5.5 2.5, 5.5 FA (fatigue) N (Nmiss) 18 (0) 18 (0) 36 (0) Mean (SD) 1.9 (0.5) 1.8 (0.3) 1.8 (0.5) Median (Q1,Q3) 1.8 (1.3,2.0) 1.7 (1.7,2.0) 1.7 (1.7,2.0) Min, Max 1.0, 3.0 1.3, 2.3 1.0, 3.0 NV (nausea and vomiting) N (Nmiss) 18 (0) 18 (0) 36 (0) 0.41 0.52 Mean (SD) 1.2 (0.3) 1.4 (0.6) 1.3 (0.5) Median (Q1,Q3) 1.0 (1.0,1.5) 1.0 (1.0,2.0) 1.0 (1.0,1.5) Min, Max 1.0, 2.0 1.0, 3.0 1.0, 3.0 PA (pain) N (Nmiss) 18 (0) 18 (0) 36 (0) 0.92 0.339 Mean (SD) 1.9 (0.6) 1.7 (0.6) 1.8 (0.6) Median (Q1,Q3) 1.5 (1.5,2.5) 1.5 (1.0,2.0) 1.5 (1.5,2.0) Min, Max 1.0, 3.0 1.0, 3.0 1.0, 3.0 DY (dyspnea) N (Nmiss) 18 (0) 18 (0) 36 (0) 1 0.337 Mean (SD) 1.7 (0.5) 1.5 (0.5) 1.6 (0.5) Median (Q1,Q3) 2.0 (1.0,2.0) 1.5 (1.0,2.0) 2.0 (1.0,2.0) Min, Max 1.0,2.0 1.0,2.0 1.0,2.0 AP (appetite loss) N (Nmiss) 18 (0) 18 (0) 36 (0) 0.13 0.722 Mean (SD) 1.9 (0.5) 1.8 (0.5) 1.9 (0.5) Median (Q1,Q3) 2.0 (2.0,2.0) 2.0 (2.0,2.0) 2.0 (2.0,2.0) Min, Max 1.0,3.0 1.0,3.0 1.0,3.0 CO (constipation) N (Nmiss) 18 (0) 18 (0) 36 (0) 2.99 0.084 Mean (SD) 1.7 (0.5) 1.4 (0.6) 1.5 (0.6) Median (Q1,Q3) 2.0 (1.0,2.0) 1.0 (1.0,2.0) 1.5 (1.0,2.0) Min, Max 1.0,2.0 1.0,3.0 1.0,3.0 DI (diarrhea) N (Nmiss) 18 (0) 18 (0) 36 (0) 0.73 0.393 Mean (SD) 1.2 (0.4) 1.3 (0.6) 1.3 (0.5) Median (Q1,Q3) 1.0 (1.0,1.0) 1.0 (1.0,2.0) 1 (1,1) Min, Max 1.0,2.0 1.0,3.0 1.0,3.0 FI (financial difficulties) N (Nmiss) 18 (0) 18 (0) 36 (0) 3.43 0.064 Mean (SD) 2.6 (0.5) 2.2 (0.6) 2.4 (0.6) Median (Q1,Q3) 3.0 (2.0,3.0) 2.0 (2.0,3.0) 2.0 (2.0,3.0) Min, Max 2.0,3.0 1.0,3.0 1.0,3.0 cellular immune function. CD4 and CD8 are two impor- partial response. DCR was defined as the percentage of tant T lymphocyte subsets. A decrease in CD4+ T lym- patients who had a complete response, partial response, phocytes indicates a decrease in lymphocyte function and and stable disease. B cell antibody production. A decrease in the CD4+/CD8+ ratio reflects a reduction in the health of the immune Adverse events system. Adverse events were reported based on the Common Terminology Criteria for Adverse Events, version 4.0. Evaluation of tumor response CT was performed 4  weeks before study initiation and Statistical analysis 9 weeks after the end of treatment to evaluate tumor size Sample size was determined according to previous obser- and status. Response rates were assessed by investiga- vations using the same primary outcome measure. Fifteen tors according to Response Evaluation Criteria in Solid participants per arm were required to detect a treatment Tumors (RECIST, version 1.1). ORR was defined as the effect with 80% power and a two-sided significance level percentage of patients who had a complete response and of 5% on the physical functioning score on the EORTC Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. SAOLP Improves HRQoL for Advanced BC Wang et al. 1071 Table 3 Baseline EORTC QLQ-BR23 scores Indicators SAOLP group Control group Total Statistic(t) P value BRBI (body image) N (Nmiss) 18 (0) 18 (0) 36 (0) 0.19 0.666 Mean (SD) 1.9 (0.6) 2 (0.5) 1.9 (0.5) Median (Q1,Q3) 1 (3.3,0) 1 (3,0) 2 (1.6,2) Min, Max 1, 3.3 1, 3 1,3.3 BRSFF (sexual functioning) N (Nmiss) 18 (0) 18 (0) 36 (0) 0.98 0.323 Mean (SD) 1.6 (0.5) 1.4 (0.5) 1.5 (0.5) Median (Q1,Q3) 1 (2,0) 1 (2,0) 1 (1,2) Min, Max 1, 2 1, 2 1, 2 BRSEE (sexual enjoyment) N (Nmiss) 11 (7) 8 (10) 36 (0) 0.73 0.394 Mean (SD) 1.9 (0.3) 2 (0) 1.9 (0.2) Median (Q1,Q3) 1 (2,0) 2 (2,0) 2 (2,2) Min, Max 1,2 2, 2 1, 2 BRFU (future perspective) N (Nmiss) 18 (0) 18 (0) 36 (0) 0.03 0.871 Mean (SD) 2.5 (0.6) 2.5 (0.5) 2.5 (0.6) Median (Q1,Q3) 2 (4,0) 2 (3,0) 2 (2,3) Min, Max 2,4 2,3 2,4 BRST (systemic therapy side effects) N (Nmiss) 18 (0) 18 (0) 36 (0) 0.41 0.521 Mean (SD) 1.6 (0.3) 1.5 (0.3) 1.6 (0.3) Median (Q1,Q3) 1.1 (2.3,0) 1 (2.1,0) 1.5 (1.3,1.9) Min, Max 1.1, 2.3 1, 2.1 1, 2.3 BRBS (breast symptoms) N (Nmiss) 18 (0) 18 (0) 36 (0) 0.19 0.662 Mean (SD) 1.6 (0.4) 1.6(0.4) 1.6 (0.4) Median (Q1,Q3) 1 (2,0) 1 (2.3,0) 1.6 (1.3,2) Min, Max 1, 2 1, 2.3 1, 2.3 BRAS (arm symptoms) N (Nmiss) 11 (7) 9 (9) 20 (16) 0.2 0.657 Mean (SD) 1.6 (0.4) 1.6 (0.4) 1.6 (0.4) Median (Q1,Q3) 1 (2.7,0) 1 (2.3,0) 1.7 (1.3,2) Min, Max 1, 2.7 1, 2.3 1, 2.7 BRHL (upset by hair loss) N (Nmiss) 14 (4) 11(7) 27 (9) 0.14 0.705 Mean (SD) 2 (0.6) 1.9 (0.5) 2 (0.5) Median (Q1,Q3) 1 (3,0) 1(3,0) 2 (2,2) Min, Max 1, 3 1, 3 1, 3 Table 4 Baseline immune response Indicators SAOLP Placebo Total Statistic(t) P value CD3 N (Nmiss) 18 (0) 18 (0) 36(0) 0.53 0.597 Mean (SD) 68.6 (10.4) 66.9 (9.5) 67.8 (9.9) Median (Q1,Q3) 66.6 (59.4,76.3) 63.8 (59.4,77.2) 65.5 (59.4,76.7) Min, Max 57.6, 89.7 54.4, 84.3 54.4, 89.7 CD4 N (Nmiss) 18 (0) 18 (0) 36 (0) 1.19 0.244 Mean (SD) 37.3 (8.3) 34.5 (5.7) 35.9 (7.2) Median (Q1,Q3) 34.4 (32.4,43.6) 34.4 (30.2,39.6) 34.4 (30.7,39.8) Min, Max 28.7, 63.0 26.9, 44.2 26.9, 63.0 CD8 N (Nmiss) 18 (0) 18 (0) 36(0) −1.49 0.145 Mean (SD) 25.4 (9.9) 29.8 (8.0) 27.6 (9.1) Median (Q1,Q3) 24.2 (20.1,28.9) 29.8 (22.3,36.5) 26.1 (20.3,35.8) Min, Max 10.9, 50.5 18.4, 43.6 10.9 (50.5) QLQ-C30 and EORTC QLQ-BR23. Accounting for a chemotherapy and SAOLP or placebo were compared 15% withdrawal and dropout rate, 36 subjects, 18 per arm, with the two-sample independent t test. Statistical were needed to ensure statistically significant results. analyses were performed with SPSS v20.0 (IBM SPSS Inc., Chicago, Illinois, USA) using a two-sided analysis. Continuous data are reported as mean, SD, median, mini- P < 0.05 was considered statistically significant. mum and maximum. Categorical variables are reported as number of cases and percentage. Standardized EORTC Results QLQ-C30 and EORTC QLQ-BR23 scores were calcu- Patient characteristics lated according to the following formulae: (1) for func- This study included 36 patients with breast cancer diag- tional items, standardized score=[1  −  (crude score−1)/ nosed based on biopsy or histology. All patients had stage range] × 100; 2) for general health and symptomatic items, IV ductal adenocarcinoma of the breast. Thirty patients standardized score=[(crude score  −  1)  ×  range]  ×  100. underwent surgery, 28 patients received preoperative Thus, for functional and general health items, a higher first-line chemotherapy, 16 patients received endocrine standardized score indicated better patient HRQoL. In treatment and 10 patients received radiotherapy. contrast, for symptomatic items, a higher standardized score indicated worse patient HRQoL. Standardized Eighteen patients each were randomized to receive EORTC QLQ-C30 and EORTC QLQ- BR23 scores SAOLP or placebo. Four patients were lost to follow-up on day 21, day 42 and day 84 for patients treated with and did not have data relevant to the primary outcome Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 1072 Anti-Cancer Drugs 2021, Vol 32 No 10 Table 5 EORTC QLQ-C30 scores on day 21, day 48 and day 84 Indicators Placebo SAOLP Statistic(t) P value Placebo SAOLP Statistic(t) P value Placebo SAOLP Statistic(t) P value (day 21) (day 21) (day 21) (day 42) (day 42) (day 42) (day 84) (day 84) (day84) (day 21) (day 42) (day 84) PF (physical function) N (Nmiss) 17 (1) 17 (1) 1.21 0.235 17 (1) 15 (3) 6.95 <0.001 17 (1) 15 (3) 7.75 <0.001 Mean (SE) 78.4(2.0) 74.9(2.1) 83.1(2.1) 58.7(2.9) 84.7(1.9) 57.3(3.1) RF (role function) N (Nmiss) 17 (1) 17 (1) 1.6 0.119 17 (1) 15 (3) 4.12 <0.001 17 (1) 15 (3) 8.36 <0.001 Mean (SE) 82.4 (5.0) 71.6 (4.5) 87.3 (4.2) 58.9 (5.6) 90.2 (3.5) 48.9 (7.0) EF (emotional functioning) N (Nmiss) 17 (1) 17 (1) 0.93 0.362 17 (1) 15 (3) 6.47 <0.001 17 (1) 15 (3) 6.76 <0.001 Mean (SE) 82.4 (4.1) 76.5 (4.9) 93.6 (2.4) 60.6 (4.7) 94.6 (2.1) 60.0 (4.9) CF (cognitive function) N (Nmiss) 17 (1) 17 (1) 1.94 0.061 17 (1) 15 (3) 2.94 0.006 17 (1) 15 (3) 6.19 <0.001 Mean (SE) 83.3 (3.2) 74.5 (3.2) 92.2 (3.2) 76.7 (4.2) 92.2 (2.9) 63.3 (3.7) SF (social function) N (Nmiss) 17(1) 17 (1) 1.71 0.096 17 (1) 15 (3) 5.6 <0.001 17 (1) 15 (3) 6.42 <0.001 Mean (SE) 68.6 (4.7) 58.8 (3.2) 79.4 (3.7) 46.7 (4.7) 80.4 (3.6) 40.0 (5.3) QL (quality) N (Nmiss) 17 (1) 17 (1) 2.56 0.015 17 (1) 15 (3) 10.53 <0.001 17 (1) 15 (3) 13.59 <0.001 Mean (SE) 60.8 (2.7) 50.0 (3.2) 78.9 (2.4) 37.2 (3.2) 81.4 (1.5) 32.8 (3.4) FA (fatigue) N (Nmiss) 17 (1) 17 (1) −1.21 0.233 17 (1) 15 (3) −6.72 <0.001 17 (1) 15 (3) −8.52 <0.001 Mean (SE) 26.1 (3.9) 32.0 (2.8) 13.1 (3.0) 51.1 (4.9) 9.8 (2.3) 62.2 (6.0) NV (nausea and vomiting) N (Nmiss) 17 (1) 17 (1) −1.37 0.18 17 (1) 15 (3) −1.92 0.0 64 17 (1) 15 (3) −2.47 0.019 Mean (SE) 6.9 (2.9) 13.7 (4.1) 4.9 (2.8) 15.6 (5.0) 4.9 (2.4) 16.7 (4.3) PA (pain) N (Nmiss) 17 (1) 17 (1) −0.32 0.754 17 (1) 15 (3) −2.3 0.029 17 (1) 15 (3) −3.39 0.002 Mean(SE) 21.6(4.7) 23.5(4.1) 14.7(3.7) 30.0(5.7) 11.8(4.0) 34.4(5.5) DY (dyspnea) N (Nmiss) 17 (1) 17 (1) −0.68 0.28 17 (1) 15 (3) −2.67 0.012 17 (1) 15 (3) −3.68 0.001 Mean (SE) 17.6 (4.2) 21.6 (4.0) 9.8 (3.8) 24.4 (3.9) 5.9 (4.3) 26.7 (3.6) AP (appetite loss) N (Nmiss) 17 (1) 17 (1) −0.65 0.518 17 (1) 15 (3) −2.91 0.007 17 (1) 15 (3) −2.23 0.033 Mean (SE) 25.5 (4.5) 29.4 (3.9) 13.7 (4.1) 28.9 (3.0) 19.6 (4.1) 33.3 (4.6) CO (constipation) N (Nmiss) 17 (1) 17 (1) 0.34 0.734 17 (1) 15 (3) −1.4 0.171 17 (1) 15 (3) −2.3 0.029 Mean (SE) 13.7 (4.1) 17.8 (4.0) 5.9 (3.2) 13.3 (4.4) 3.9 (2.7) 15.6 (4.4) DI (diarrhea) N (Nmiss) 17 (1) 17 (1) −0.79 0.434 17 (1) 15 (3) −2.05 0.049 17 (1) 15 (3) −2.61 0.014 Mean (SE) 5.9 (3.2) 9.8 (3.8) 2.0 (2.0) 11.1 (4.2) 0 (0) 13.3 (5.4) FI (financial difficulties) N (Nmiss) 17 (1) 17 (1) 0.3 0.765 17 (1) 15 (3) −2.06 0.048 17 (1) 15 (3) −4.67 <0.001 Mean (SE) 49.0 (4.2) 47.1 (5.0) 41.2 (3.5) 57.8 (7.6) 35.3 (4.5) 71.1 (6.4) Table 6 EORTC QLQ-BR23 scores on day 21, day 48 and day 84 Indicators SAOLP Placebo Statistic(t) SAOLP Placebo Statistic(t) SAOLP Placebo Statistic(t) P value P value P value (day 21) (day 21) (day 21) (day 21) (day 42) (day 42) (day 42) (day 42) (day 84) (day 84) (day84) (day 84) BRBI (body image) N (Nmiss) 17 (1) 17 (1) 2.1 0.044 17 (1) 15 (3) 6.98 <0.001 17 (1) 15 (3) 7.08 <0.001 Mean (SE) 77.9 (4.3) 64.2 (4.9) 83.8 (4.0) 45.0 (3.8) 85.8 (3.3) 46.7 (4.6) BRSFF (sexual functioning) N (Nmiss) 17 (1) 17 (1) −1.02 0.315 17 (1) 15 (3) −1.37 0.181 17 (1) 15 (3) −1.37 0.181 Mean (SE) 82.4 (4.2) 88.2 (4.0) 83.3 (4.0) 91.1 (3.9) 83.3 (4.0) 91.1 (3.9) BRSEE (sexual enjoyment) N (Nmiss) 10 (8) 6 (12) 0.76 0.458 10 (8) 10 (8) −1.9 0.074 11 (7) 10 (8) −1.53 0.144 Mean (SE) 70.0 (3.3) 66.7 (0) 73.3 (4.4) 86.7 (5.4) 75.8 (4.7) 86.7 (5.4) BRFU (future perspective) N (Nmiss) 17 (1) 17 (1) 2.58 0.015 17 (1) 15 (3) 4.36 <0.001 17 (1) 15 (3) 6.14 <0.001 Mean (SE) 58.8 (3.5) 45.1 (4.0) 66.7 (5.0) 35.6 (5.1) 68.6 (4.5) 22.2 (6.2) BRST (systemic therapy N (Nmiss) 17 (1) 17 (1) −0.47 0.641 17 (1) 15 (3) −2.92 0.007 17 (1) 15 (3) −4 <0.001 side effects) Mean (SE) 18.2 (2.3) 19.9 (2.7) 12.6 (3.0) 25.1 (3.0) 11.5 (2.3) 26.7 (3.0) BRBS (breast symptoms) N (Nmiss) 17 (1) 17 (1) −0.42 0.675 16 (2) 15 (3) −4.07 <0.001 17 (1) 15 (3) −5.21 <0.001 Mean (SE) 19.6 (2.7) 21.6 (3.8) 12.0 (2.7) 30.6 (3.7) 8.3 (2.3) 30.0 (3.6) BRAS (arm symptoms) N (Nmiss) 17 (1) 17 (1) −0.68 0.502 17 (1) 15 (3) −1.98 0.0 57 17 (1) 15 (3) −2.72 0.011 Mean (SE) 17.6 (2.7) 20.3 (2.7) 15.7 (2.5) 23.7 (3.2) 14.4 (2.3) 25.2 (3.3) BRHL (upset by hair loss) N (Nmiss) 12 (6) 12 (6) −0.69 0.496 8 (10) 10 (8) −1.56 0.138 11 (7) 11 (7) −1.78 0.091 Mean (SE) 33.3 (7.1) 38.9 (3.7) 29.2 (11.7) 50.0 (7.5) 24.2 (9.1) 42.4 (4.7) measure; therefore, data from 32 patients were included EORTC QLQ-C30 on day 21, day 42 and day 84 On day 21, the score on the global health status/QoL in the final analysis (Fig. 1). scale was significantly higher in patients who received The demographic and baseline characteristics of the SAOLP compared to placebo. There were no signif- included patients are summarized in Table  1. Patients icant differences in scores on the functional scales had a median age of 55.4 years (range 49.2–63.7). 22.2% or the symptom scales. On day 42, scores on the five of patients received first-line chemotherapy, and 77.8% functional scales (physical, role, cognitive, emotional of patients received second- or later-line chemotherapy. and social) and the global health status/QoL scale were significantly higher in patients who received EORTC QLQ-BR23 SAOLP compared to placebo (P < 0.05). Scores on six There were no significant differences in baseline EORTC of the symptom scales (fatigue, pain, dyspnea, loss of QLQ-C30 (Table  2), EORTC QLQ-BR23 (Table  3) or appetite, diarrhea and financial difficulties) were sig- immune response in patients who received SAOLP or nificantly lower in patients who received SAOLP com- placebo (Table 4). pared to placebo (P  <  0.05). On day 84, scores on the Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. SAOLP Improves HRQoL for Advanced BC Wang et al. 1073 Table 7 Immune response on day 21, day 48, and day 84 Indicators SAOLP (day 21) Placebo (day 21) Statistic(t) P value CD3 N (Nmiss) 17 (1) 17 (1) 1.86 0.073 Mean (SE) 70.5 (2.3) 64.4 (2.4) CD4 N (Nmiss) 17 (1) 17 (1) 2.05 0.049 Mean (SE) 36.7 (1.4) 32.9 (1.1) CD8 N (Nmiss) 17 (1) 17 (1) 1.25 0.219 Mean (SE) 30.1 (2.6) 25.9 (2.1) CD4/CD8 N (Nmiss) 17 (1) 17 (1) 0.15 0.879 Mean (SE) 1.38 (0.14) 1.36 (0.08) Indicators SAOLP (day 42) Placebo (day 42) Statistic(t) P value CD3 N (Nmiss) 17 (1) 14 (3) 10.47 <0.001 Mean (SE) 76.1 (1.4) 59.0 (5.0) CD4 N (Nmiss) 17 (1) 14 (3) 6.12 <0.001 Mean (SE) 39.2 (1.4) 29.0 (0.6) CD8 N (Nmiss) 17 (1) 14 (3) 5.52 <0.001 Mean (SE) 34.6 (2.3) 20.5 (0.6) CD4/CD8 N (Nmiss) 17 (1) 14 (3) −2.02 0.055 Mean (SE) 1.22 (0.09) 1.43 (0.04) Indicators SAOLP (day 84) Placebo (day 84) Statistic(t) P value CD3 N (Nmiss) 17 (1) 14 (4) 15.1 <0.001 Mean (SE) 77.8 (1.2) 57.7 (0.4) CD4 N (Nmiss) 17 (1) 14 (4) 5.31 <0.001 Mean (SE) 42.0 (1.5) 29.0 (2.2) CD8 N (Nmiss) 17 (1) 14 (4) 8.82 <0.001 Mean (SE) 36.9 (1.8) 18.9 (0.3) CD4/CD8 N (Nmiss) 17 (1) 14 (4) −2.58 0.015 Mean (SE) 1.20 (0.07) 1.53 (0.11) Table 8 BMI on day 21, day 48 and day 84 Immune response on day 21, day 42 and day 84 On day 21, there were no significant differences in the Indicators SAOLP Placebo Statistic(t) P value number of CD3, CD4 or CD8 cells or the CD4/CD8 BMI_Day 21 N (Nmiss) 17 (1) 17 (1) 0.06 0.951 ratio in patients who received SAOLP or placebo. On Mean (SE) 23.7 (0.7) 23.6 (0.7) day 42, the number of CD3, CD4 and CD8 cells were BMI_Day 42 N (Nmiss) 17 (1) 15 (3) 0.2 0.84 Mean (SE) 23.4 (0.8) 23.2 (0.7) significantly higher in patients who received SAOLP BMI_Day 84 N (Nmiss) 17 (1) 15 (3) 1.49 0.147 compared to placebo (P  <  0.05). On day 84, the num- Mean (SE) 23.6 (0.7) 22.2 (0.5) ber of CD3, CD4 and CD8 cells and the CD4/CD8 ratio were significantly higher in patients who received five functional scales (physical, role, cognitive, emo- SAOLP compared to placebo (P < 0.05) (Table 7). tional and social) and the global health status/QoL scale were significantly higher in patients who received Objective effective rate and disease control rate SAOLP compared to placebo (P < 0.05). Scores on the ORR was 7.1% and 8.3% (P  =  1.000) in patients who nine symptom scales (fatigue, pain, nausea and vomit- received SAOLP or placebo, respectively. DCR was 100 ing, dyspnea, loss of appetite, insomnia, constipation, and 83.3% (P = 0.203) in patients who received SAOLP diarrhea and financial difficulties) were significantly or placebo, respectively. There were no significant differ - lower in patients who received SAOLP compared to ences in ORR or DCR in patients who received SAOLP placebo (Table 5). or placebo (Table 8). EORTC QLQ-BR23 on day 21, day 42 and day 84 BMI On day 21, scores on two of the functional scales (body On day 21, day 42 and day 84, BMI was higher in patients image and future perspective) were significantly higher who received SAOLP compared to placebo, but the dif- in patients who received SAOLP compared to placebo ferences were NS. (P  <  0.05). On day 42, scores on two of the functional scales (body image and future perspective) were signif- Safety icantly higher and scores on two of the symptom scales Across all enrolled patients, 47.22% (17/36) of patients (systemic therapy side effects and breast symptoms) were reported an adverse event. Most of the adverse events significantly lower in patients who received SAOLP com- were Grade 1 or 2. Frequent nonhematological toxici- pared to placebo (P < 0.05). On day 84, scores on two of ties included nausea/vomiting, fatigue and proteinuria. the functional scales (body image and future perspec- Among patients who received SAOLP, 50% (9/18) of tive) were significantly higher and scores on three of the patients reported an adverse event. Among patients who symptom scales (systemic therapy side effects, breast received placebo, 44.4% (8/18) of patients reported an symptoms and arm symptoms) were significantly lower adverse event. No patients reported a serious drug-re- in patients who received SAOLP compared to placebo lated adverse event. All adverse events were considered (P < 0.05) (Table 6). related to chemotherapy. Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 1074 Anti-Cancer Drugs 2021, Vol 32 No 10 cancer. SAOLP represents a convenient and safe adju- Discussion vant therapy. This clinical trial was designed to evaluate the safety and efficacy of SAOLP for improving HRQoL and immune Acknowledgements response during chemotherapy in Chinese patients with This study was supported by grants from Beijing Key breast cancer. Breast cancer treatment involves a mul- Specialty (Bangwei Cao). timodal approach that includes chemotherapy [15]. Chemotherapy can significantly improve survival and qual- ity of life compared to best supportive care in patients with All authors contributed to the study’s conception and design. Material preparation, data collection and analy- breast cancer [16–18]. However, adverse effects of chemo- sis were performed by J.W., X.M., K.S., S.W., Y.M., Z.M. therapy in patients with malignant tumors include fatigue, and B.C. The first draft of the manuscript was written by nausea and vomiting, bone marrow suppression, renal J.W., and all authors commented on previous versions of toxicity, neurotoxicity and cancer-related cognitive impair- the manuscript. All authors read and approved the final ment [19]. Accordingly, most patients with breast cancer manuscript. experience a decline in HRQoL due to tumor burden and treatment effects, such as loss of appetite, reduction in Conflicts of interest body mass and emotional instability. Improving the quality There are no conflicts of interest. of life of patients with cancer is essential to decrease psy- chological distress and enhance coping [20,21]. 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Published: Nov 12, 2021

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