Exploring the Relationship Between Anorexia and Therapeutic Efficacy in Advanced Lung Cancer Treatment: A Retrospective Study

Exploring the Relationship Between Anorexia and Therapeutic Efficacy in Advanced Lung Cancer Treatment: A Retrospective Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Exploring the Relationship Between Anorexia and Therapeutic Efficacy in Advanced Lung Cancer Treatment: A Retrospective Study Kosei Doshita, Tateaki Naito, Suguru Matsuda, Meiko Morita, Motoki Sekikawa, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4106256/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Chemotherapy-induced anorexia is frequently observed in patients with advanced lung cancer who are receiving chemotherapy. This study explored the relationship between chemotherapy-induced anorexia and therapeutic outcomes in patients with stage IV non-small cell lung cancer undergoing platinum-based chemotherapy combined with immune checkpoint inhibitors. Methods We retrospectively reviewed the medical records of 106 patients with stage IV non-small cell lung cancer treated with platinum-based chemotherapy combined with immune checkpoint inhibitors between January 2019 and October 2022. The incidence of weight loss and its association with treatment efficacy was assessed in the chemotherapy-induced anorexia group. Chemotherapy-induced anorexia and chemotherapy-induced nausea and vomiting were evaluated using Common Terminology Criteria for Adverse Events version 5.0. Progression-free and overall survival were used to measure treatment efficacy. Results Chemotherapy-induced anorexia was observed in 13.2% of patients. Patients with chemotherapy-induced anorexia showed significant weight loss at 6 and 9 weeks after treatment initiation compared to those in the non-chemotherapy-induced anorexia group. Progression-free and overall survival were shorter in the chemotherapy-induced anorexia group than in the non-chemotherapy-induced anorexia group, but the difference was not statistically significant. Conclusions Chemotherapy-induced anorexia was associated with significant weight loss and reduced treatment efficacy in patients with stage IV non-small cell lung cancer. These findings suggest the need for aggressive supportive therapy for chemotherapy-induced anorexia to prevent weight loss and maintain therapeutic efficacy during platinum-based chemotherapy combined with immune checkpoint inhibitors. Chemotherapy-induced anorexia immune checkpoint inhibitors non-small cell lung cancer platinum-based chemotherapy treatment efficacy Figures Figure 1 Figure 2 Figure 3 Background Lung cancer is the leading cause of cancer-related deaths worldwide [ 1 ]. Cancer-associated weight or skeletal muscle loss is commonly observed in patients with advanced lung cancer undergoing chemotherapy [ 2 ]. Cancer chemotherapy regimens frequently cause weight and skeletal muscle loss [ 3 ], partly due to chemotherapy-induced anorexia (CIA) or chemotherapy-induced nausea and vomiting (CINV), which are among the most unpleasant adverse events. However, there is no clear definition of CIA, which is characterized by early satiety or a decrease or loss of physiological desire to consume food. CIA is associated with the systemic impact of cancer-induced weight loss and results in worsening performance status (PS) and quality of life (QOL) [ 4 – 6 ]. In contrast to CINV, the assessment and management of CIA is currently not incorporated into the routine supportive care pathway for patients receiving platinum-based chemotherapy. Even with the implementation of standard antiemetic therapy for the control of CINV, complete response (CR; no vomiting, no use of rescue medication) and complete control (CC; CR + no significant nausea) rates ranged from 40–75% [ 7 – 9 ]. A randomized controlled phase III trial evaluating the efficacy of adding olanzapine to a triple-drug antiemetic regimen (the J-FORCE trial) reported a high incidence of anorexia (63.2%), despite a 79% CR for CINV in the olanzapine group [ 10 ]. In addition, CIA potentially affects oncologic outcomes of chemotherapy. Previous studies have reported that weight loss diminishes the therapeutic effects of immune checkpoint inhibitors (ICI) used either as monotherapy or in combination with platinum-based chemotherapy for the treatment of stage IV non-small cell lung cancer (NSCLC) [ 11 – 13 ], and a correlation between anorexia and weight loss has been observed in the context of chemotherapy [ 4 ]. To date, there have been no investigations on the relationship between CIA and weight loss during platinum-based chemotherapy combined with ICIs for stage IV NSCLC. Therefore, the purpose of this study was to elucidate the incidence of CIA and the frequency of weight loss in patients with stage IV NSCLC receiving platinum-based chemotherapy combined with immune therapy and standard antiemetic therapy. In addition, this study also sought to determine whether CIA leads to weight loss and whether it is associated with treatment effectiveness. Methods Study design and patients This retrospective study included patients with stage IV NSCLC treated with first-line platinum-based chemotherapy combined with ICIs. We retrospectively reviewed the medical records of consecutive patients treated at Shizuoka Cancer Center between January 2019 and October 2022. Disease stage was determined according to the TNM classification (8th edition) proposed by the International Association for the Study of Lung Cancer [ 14 ]. This retrospective study was approved by the Institutional Ethical Review Board of Shizuoka Cancer Center (J2023-105-2023-1). Patients were able to opt out of the study. Data collection and response evaluation The following patient data at the start of first-line chemotherapy were obtained from medical records: age, sex, smoking status, Eastern Cooperative Oncology Group performance status (ECOG PS), histology, programmed cell death ligand 1(PD-L1) status, clinical stage, body weight (at the start of and 6 months before first-line chemotherapy), height, type of platinum agent, dose used in first-line chemotherapy, type of concomitant anticancer drug and dose used in first-line chemotherapy, type of immune checkpoint inhibitor, tumor response to first-line chemotherapy, duration from the start of platinum doublet chemotherapy to the last date of platinum doublet chemotherapy, treatment interval of each course, dose reduction, treatment cessation, dose delivery (defined as the effectively delivered chemotherapy dose considering all reductions and omissions) of each anticancer drug, date of death, or any recurrences detected with any imaging modality or the last visit. The best tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, version 1.1 [ 15 ]. Chemotherapy regimens The patients received platinum-based chemotherapy combined with ICIs. The following platinum-based regimens were used: Cisplatin (CDDP) (75 mg/m 2 on day 1) and pemetrexed (PEM) (500 mg/m 2 on day 1); carboplatin (CBDCA) (area under the blood concentration time curve [AUC] = 5 on day 1) and PEM (500 mg/m 2 on day 1); CBDCA (AUC = 6 on day 1) and paclitaxel (PTX) (200 mg/m 2 on day 1); CBDCA (AUC = 6 on day 1) and nab-PTX (100 mg/m 2 on day 1); or CBDCA (AUC = 6 on day 1), PTX (200 mg/m 2 on day 1), and bevacizumab (Bev) (15 mg/m 2 on day 1) for up to four courses followed by either concomitant anticancer drugs or ICIs as maintenance therapy. Pembrolizumab was combined with CDDP, CBDCA + PEM, CBDCA + PTX or nab-PTX. Atezolizumab was administered with CBDCA + PEM, CBDCA + PTX, CBDCA + nab-PTX, and CBDCA + PTX + bevacizumab. Nivolumab and ipilimumab were administered with CBDCA + PEM. One-step dose reduction of the platinum agent and/or concomitant anticancer drug was performed for grade 4 hematologic toxicity, grade 3 febrile neutropenia, or grade 3 non-hematologic toxicity (except nausea, anorexia, hyponatremia, weight loss, alopecia, and constipation). Dose reduction was also allowed at the physician’s discretion. Antiemetic therapy The enrolled patients received standard antiemetic therapy (palonosetron, aprepitant, and dexamethasone) and olanzapine on or after the administration of the first course of chemotherapy. Palonosetron was administered intravenously at a dose of 0.75 mg 30–60 min before chemotherapy on day 1. Aprepitant was administered orally at a dose of 25 mg 60–90 min before chemotherapy on day 1 and at a dose of 80 mg on days 2 and 3. Dexamethasone was administered intravenously at a dose of 9.9 mg 30–60 min before chemotherapy on day 1 and then orally at a dose of 8 mg on days 2–4. Olanzapine was administered orally at a dose of 5 mg once daily after dinner on days 1–4 or 1–5. The decision to administer olanzapine prophylactically from the initial treatment was based on the physician’s decision. Assessments Nutritional assessment Body weight (kg) was measured to the nearest 0.1 kg, and the body mass index (BMI) was subsequently calculated as body weight(kg)/[height (m)] 2 at baseline, 6 weeks, and 9 weeks after initiating chemotherapy. Assessment of chemotherapy-induced nausea and vomiting CINV was evaluated based on the proportion of patients who did not experience nausea or vomiting and did not require additional treatment with antiemetics. Doctors or nurses reported nausea and vomiting in electronic medical records using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 as follows: Nausea: grade 1, loss of appetite without alteration in eating habits; grade 2, decreased oral intake without significant weight loss, dehydration, or malnutrition; grade 3, inadequate oral caloric or fluid intake; tube feedings, total parenteral nutrition (TPN), or hospitalization indicated. Vomiting: grade 1, intervention not indicated; grade 2, outpatient intravenous hydration; medical intervention indicated; grade 3, tube feeding, TPN, or hospitalization indicated; grade 4, life-threatening consequences. Total control (TC) of CINV was defined as the absence of nausea and vomiting without additional treatment with antiemetics during the 0–168 h period after the first course of chemotherapy. Patients were classified into the TC group if their CINV was completely controlled during the first course of chemotherapy; otherwise, they were classified into the non-TC group. In this study, we evaluated CINV for the first 168 h, which is longer than that reported previously. In previous reports on CINV and CIA during the first 5 days (120 h) after the start of treatment, control of CINV and CIA on day 5 was incomplete and gastrointestinal symptoms of CINV and CIA persisted after day 5 [ 10 ]. Therefore, in this study, the CINV/CIA observation period was set at 7 days (168 h) from the start of the treatment. Assessment of chemotherapy-induced anorexia CIA was defined as decreased appetite during the 0–168 h period after the first course of chemotherapy. Doctors or nurses reported anorexia on electronic medical records using the CTCAE version 5.0 as follows: grade 1, loss of appetite without alteration in eating habits; grade 2, oral intake altered without significant weight loss or malnutrition with oral nutritional supplements indicated; grade 3, associated with significant weight loss or malnutrition (e.g., inadequate oral caloric and/or fluid intake) with tube feeding or TPN indicated; and grade 4, life-threatening consequences requiring urgent intervention. Because grade 2 or higher anorexia affects oral intake, patients were classified into the CIA group if their appetite loss worsened from anorexia grade 0–1 to grade ≥ 2 during the 0–168 h period following the initiation of chemotherapy, and patients were classified into the non-CIA group if they had no anorexia or their worst anorexia grade during the 0–168 h period after chemotherapy initiation was 1. Assessment of treatment delivery The median duration of chemotherapy was defined as the period from the first day of chemotherapy to the day of the last chemotherapy dose in the final cycle. The treatment interval was the date from the last chemotherapy dose in each course to the first day of the next course. Relative dose intensity (total dose received over actual treatment duration divided by the total dose prescribed by the planned over the theoretical treatment period) was calculated as described by Lorigan et al. [ 16 ] Dose reduction was considered to have occurred if there was at least one dose reduction during the treatment period. Other events were collected if the interval between treatment cycles was more than 1 week longer than expected, or if treatment was stopped for reasons other than disease progression. Statistical analyses The primary outcomes were changes in body weight and BMI. The secondary outcomes were dose delivery (relative dose intensity, incidence of dose reduction, or treatment delay or cessation), overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Patient characteristics were compared both descriptively and statistically using Fisher’s exact test for categorical variables and the Wilcoxon test for continuous variables. ORR was calculated as the complete plus partial response rate, which was measured using RECIST ver. 1.1. OS and PFS were measured as the intervals between the start of first-line chemotherapy and death, or any recurrence detected with any imaging modality or the last visit, respectively. Survival curves were plotted using the Kaplan–Meier method and compared using standard log-rank tests. Data for patients without disease progression or who were lost to follow-up were censored at the last visit. A two-sided p-value < 0.05 was considered statistically significant. JMP (ver. 14.0, SAS Institute) software was used for statistical analyses. Results Patient characteristics From January 2019 to October 2022, 110 patients with stage IV NSCLC were treated with combination therapy including an ICI and platinum doublet chemotherapy. Four patients were excluded from this study because of a lack of information on body weight at 6 and 9 weeks after the initiation of the first course of chemotherapy (Fig. 1). The median follow-up duration was 389 days (95% confidence interval [CI]: 319–470 days). The median age was 67.5 years, 81 (76.4%) were male, 105 (99.1%) had good PS (ECOG-PS 0–1), and 94 (88.7%) were current or former smokers. The most common histological types were adenocarcinoma (n=82, 77.4%) and squamous cell carcinoma (n=14, 13.2%). Twenty-one (19.8%) patients had more than 5% body weight loss 6 months before the start of first-line chemotherapy. Patient characteristics at the start of the first-line chemotherapy are shown in Table 1. Table 1. Patient characteristics All patient (n=106) non-CIA (n=92) CIA (n=14) p-value TC (n=76) non-TC (n=30) p-value Age (years) Median (range) 67.5 (36–85) 67.5 (36–85) 66.5 (57–74) 0.815 68 (36–85) 64.5 (50–83) 0.277 Sex, n (%) Male Female 81 (76.4) 25 (23.6) 69 (75.0) 23 (25.0) 12 (85.7) 2 (14.3) 0.511 57 (75.0) 19 (25.0) 24 (80.0) 6 (20.0) 0.799 ECOG-PS, n (%) 0 1 2 24 (22.6) 81 (76.4) 1 (0.9) 23 (25.0) 68 (73.9) 1 (1.1) 1 (7.1) 13 (92.9) 0 (0.0) 0.290 20 (26.3) 55 (72.4) 1 (1.3) 4 (13.3) 26 (86.7) 0 (0.0) 0.314 Histopathology, n (%) Ad Sq Other 82 (77.4) 14 (13.2) 10 (9.4) 73 (79.4) 11 (12.0) 8 (8.7) 9 (64.3) 3 (21.4) 2 (14.3) 0.184 60 (79.0) 11 (14.5) 5 (6.6) 22 (73.3) 3 (10.0) 5 (16.7) 0.281 PD-L1 status, n (%) ≥50% 1-49% <1% unknown 11 (10.4) 31 (29.2) 59 (55.7) 5 (4.7) 10 (10.9) 26 (28.3) 51 (55.4) 5 (5.4) 1 (7.1) 5 (35.7) 8 (57.1) 0 (0.0) 0.959 10 (13.2) 21 (27.6) 40 (52.6) 5 (6.6) 1 (3.3) 10 (33.3) 19 (63.3) 0 (0.0) 0.236 Stage, n (%) ⅣA ⅣB 51 (48.1) 55 (51.9) 45 (48.9) 47 (51.1) 6 (42.9) 8 (57.1) 0.778 40 (52.6) 36 (47.4) 11 (36.7) 19 (63.3) 0.195 Smoking status, n (%) Current/former Never 94 (88.7) 12 (11.3) 81 (88.0) 11 (12.0) 13 (92.9) 1 (7.1) 1.000 67 (88.2) 9 (11.8) 27 (90.0) 3 (10.0) 1.000 BMI (kg/m 2 ) Median (range) 21.2 (15.7–35.3) 21.7 (15.7–33.9) 19.6 (17.4–35.3) 0.334 21.5 (15.7–35.3) 20.6 (16.4–26.3) 0.285 ≥5％ Body weight loss in previous 6 months Yes No Unknown 21 (19.8) 40 (37.7) 45 (42.5) 16 (17.4) 35 (38.0) 41 (44.6) 5 (35.7) 5 (35.7) 4 (28.6) 0.271 15 (19.7) 30 (39.5) 31 (40.8) 6 (20.0) 10 (33.3) 14 (46.7) 0.818 Platinum agent CDDP CBDCA 30 (34.0) 76 (66.0) 29 (31.5) 63 (68.5) 7 (50.0) 7 (50.0) 0.227 24 (31.6) 52 (68.4) 12 (40.0 18 (60.0) 0.496 Concomitant anticancer drug, n (%) PEM nab-PTX PTX PTX+Bev 81 (76.4) 14 (13.2) 5 (4.7) 6 (5.7) 73 (79.4) 11 (12.0) 4 (4.4) 4 (4.4) 8 (57.1) 3 (21.4) 1 (7.1) 2 (14.3) 0.119 58 (76.3) 10 (13.2) 4 (5.3) 4 (5.3) 23 (76.7) 4 (13.3) 1 (3.3) 2 (6.7) 1.000 Concomitant Immune checkpoint inhibitor, n (%) Pembrolizumab Atezolizumab Nivo+Ipi 89 (84.0) 16 (15.1) 1 (0.9) 78 (84.8) 13 (14.1) 1 (1.1) 11 (78.6) 3 (21.4) 0.518 64 (84.2) 11 (14.5) 1 (1.3) 25 (80.0) 5 (20.0) 0.836 Use of Olanzapine on days 1–8 of the first course of treatment, n (%) Yes No Preventive use 24 (22.6) 82 (77.4) 18 (17.0) 18 (19.6) 74 (80.4) 16 (17.4) 6 (42.9) 8 (57.1) 2 (14.3) 0.081 1.000 12 (15.8) 64 (84.2) 6 (7.9) 12 (40.0) 18 (60.0) 6 (20.0) 0.011 0.579 Abbreviation: ECOG-PS, Eastern Cooperative Oncology Group Performance; Ad, adenocarcinoma; Sq, squamous cell carcinoma; PD-L1, programmed cell death ligand 1; BMI, body mass index; CDDP, cisplatin; CBDCA, carboplatin; PEM, pemetrexed; PTX, paclitaxel; Bev, bevacizumab; Nivo, nivolumab; Ipi, ipilimumab. Frequency of CINV and CIA Among the 106 patients, 14 (13.2%) and 30 (28.3%) were classified into the CIA and non-TC groups, respectively. Of these, 10 in the CIA group (10/14, 71.4%) were in the non-TC group and 10 in the non-TC group (10/30, 33.3%) were in the CIA group (Pearson's chi-square test, p=0.0001) (Supplementary Table A1). There were no significant between-group differences in clinicopathological characteristics, such as age, sex, ECOG-PS, tumor histology, PD-L1 status, clinical stage, smoking status, baseline BMI, frequency of body weight loss ≥ 5% in the previous 6 months, and drugs used (platinum agents, concomitant anticancer drugs, and ICIs). The use of olanzapine on days 1–8 of the first course of treatment was not significantly different between the CIA and non-CIA groups, but was more frequent in the non-TC than in the TC group. There was no significant group difference in the preventive use of olanzapine. Dose delivery and therapy duration There were no significant differences in the type of platinum agent used (CDDP use: CIA, 7 [50.0%] vs. non-CIA, 29 [31.5%]; p=0.23); non-TC, 12 [40.0%] vs. TC, 24 [31.6%]; p=0.50), mean duration of platinum doublet chemotherapy, treatment interval per course, or cycles of platinum doublet chemotherapy. There was no difference in the median number of cycles for platinum doublet chemotherapy administration: 4 (range: 3–4) in the CIA group, 4 (range: 4–4) in the non-CIA group (p=0.80), 4 (range: 4–4) in the non-TC group, and 4 (range: 3–4) in the TC group (p=0.34). The median number of cycles for maintenance therapy administration was significantly lower in the CIA than in the non-CIA group (5, range: 3–6 vs. 8, range: 5–15; p=0.01), but not in the non-TC and TC groups (4, range: 4–4 vs. 4, range: 3–4; p=0.34). The relative dose delivery intensity of platinum agents and combination anticancer drugs was 100% in the CIA (interquartile range [IQR]: 100–100) and non-CIA groups (IQR: 87.5–100), and that of concomitant anticancer drugs was 100% in the CIA (IQR: 100–100) and non-CIA groups (IQR: 85.9–100). Notably, both were significantly lower in the CIA group (p<0.01). In addition, the frequency of dose reduction within the first four cycles for platinum agents and concomitant anticancer drugs was significantly higher in the CIA group than in the non-CIA group (platinum agent: 2.2% vs. 28.6%, p<0.01; concomitant anticancer drugs: 4.4% vs. 28.6%, p=0.01). No significant differences in the frequency of dose reduction were observed between the TC and non-TC groups (platinum agent: 4.0% vs. 10.0%, p=0.35. concomitant anticancer drugs: 5.3% vs. 13.3%, p=0.22). There was no significant between-group difference in the frequency of dose delays of ≥1 week or treatment cessation (Table 2). Table 2. Dose intensity by CIA/TC group non-CIA (n=92) CIA (n=14) p-value TC (n=76) non-TC (n=30) p-value Concomitant platinum-agent, n (%) CDDP CBDCA 29 (31.5) 63 (68.5) 7 (50.0) 7 (50.0) 0.23 24 (31.6) 52 (68.4) 12 (40.0) 18 (60.0) 0.50 Mean duration of platinum-doublet therapy [weeks] Median (IQR) 9.7 (9–11.4) 9.9 (8.9–12.0) 0.11 9.1 (9–11) 10.1 (9.2–12) 0.07 Treatment interval / course (days) Median (range) 23.3 (21–27.3) 23.0 (21.3–28.1) 0.90 22.8 (21–27.3) 23.5 (21.3–28) 0.42 Cycles for platinum-doublet therapy Median (IQR) 4 (4–4) 4 (3–4) 0.80 4 (4–4) 4 (4–4) 0.34 Cycles for maintenance therapy Median (IQR) 8 (5–15) 5 (3–6) 0.01 8 (4–15) 6 (5–10) 0.25 Platinum-agent Relative dose intensity (%) Median (IQR) 100 (100–100) 100 (87.5–100) <0.01 100 (100–100) 100 (100–100) 0.22 Dose reduction a [within 4 cycles], n (%) 2 (2.2) 4 (28.6) <0.01 3 (4.0) 3 (10.0) 0.35 Combination anticancer drug Relative dose intensity (%) Median (IQR) 100 (100–100) 100 (85.9–100) <0.01 100 (100–100) 100 (100–100) 0.14 Dose reduction b [within 4 cycles], n (%) 4 (4.4) 4 (28.6) 0.01 4 (5.3) 4 (13.3) 0.22 Dose delays ≥1 week / cycle [within 4 cycles], n (%) 47 (51.1) 5 (35.7) 0.39 36 (47.4) 16 (53.3) 0.67 Treatment cessation [not PD, within 4 cycles], n (%) 12 (13.0) 3 (21.4) 0.42 11 (14.5) 4 (13.3) 1.00 a Reasons for dose reductions: Grade 3 anorexia (3), Grade 3 febrile neutropenia (2), and Grade 2 rash (1). b Reasons for dose reductions: Grade 3 anorexia (3), Grade 3 febrile neutropenia (2), Grade 2 rash (2), and Grade 2 peripheral sensory neuropathy. Impact of CIA and CINV on body weight and BMI The change in weight from baseline was significantly different between the CIA and non-CIA groups 6 and 9 weeks after treatment initiation (6 weeks: -4.28% vs. 0.36%, p=0.012; 9 weeks: -2.90% vs. 2.20%, p=0.007) (Fig. 2a), but not between the non-TC and TC groups (6 weeks: 0.39% vs. 0.34%, p=0.988; 9 weeks: 2.66 vs. 1.71, p=0.492) (Fig. 2b). The change in BMI from baseline was also significantly different between the CIA and non-CIA groups 6 and 9 weeks after treatment initiation (6 weeks: -0.79 vs. 0.07, p=0.011; -0.56 vs. 0.45; p=0.011) (Fig. 2c), but not between the non-TC and TC groups (6 weeks: 0.07 vs. 0.07, p=0.994; 9 weeks: 0.47 vs. 0.40, p=0.627) (Fig. 2d, Table 3). Table 3. Body weight and BM I non-CIA (n=92) CIA (n=14) p-value TC (n=76) non-TC (n=30) p-value Change in weight from baseline (%) 6 weeks after treatment initiation (IQR) (missing value=2) 0.36 (-1.75–2.73) -4.28 (-8.89–0.47) 0.012 0.34 (-2.56–2.57) 0.39 (-3.02–2.39) 0.988 9 weeks after treatment initiation (IQR) (missing value=4) 2.20 (-1.14–4.44) -2.90 (-11.0–3.29) 0.007 1.71 (-2.30–3.64) 2.66 (-1.85–4.72) 0.492 Change in BMI from baseline (kg/m 2 ) 6 weeks after treatment initiation (IQR) 0.07 (-0.40–0.63) -0.79 (-1.93–0.09) 0.011 0.07 (-0.57–0.55) 0.07 (-0.61–0.47) 0.994 9 weeks after treatment initiation (IQR) 0.45 (-0.23–0.96) -0.56 (-2.27–0.64) 0.007 0.40 (-0.55–0.86) 0.47 (-0.38–0.95) 0.627 Abbreviations: BMI, body mass index; CIA, chemotherapy-induced anorexia; IQR, interquartile range; TC, total control. Efficacy At the time of data cutoff (October 20, 2023), the median follow-up duration from the start of first-line chemotherapy for censored cases was 389 days (95% CI: 319–470 days). Of the 106 included patients, 36 (34.0%) had died at the time of the data cutoff. For the entire cohort, the median PFS was 236.5 days (95% CI: 176–290 days). Although the non-CIA group showed better PFS than the CIA group (median PFS: 258.5 days vs. 123.5 days, HR: 0.57, 95% CI: 0.31–1.03, p=0.06; Fig. 3a), the difference was not statistically significant. There was no significant difference in PFS between the TC and non-TC groups (median PFS: 236.5 days vs. 237 days; HR, 0.70; 95% CI: 0.45–1.10, p=0.12; Fig. 3b). OS was also better in the non-CIA group than in the CIA group (median OS: 640 vs. 394.5 days, HR: 0.67, 95% CI: 0.35–1.29, p=0.23; Fig. 3c), however, the difference was not statistically significant. In addition, there was no significant difference in OS between the TC and non-TC groups (median OS, 458 vs. 610 days; HR, 0.97; 95% CI: 0.58–1.63, p=0.91; Fig. 3d). The ORR and PFS stratified according to CIA/non-CIA and TC/non-TC groups are shown in Supplementary Table A1. Among patients with TC (n=76), the non-CIA group had a higher ORR (48.6% vs. 25.0, p=0.617), although the difference was not statistically significant, and longer PFS (262 days vs. 91 days, p<0.0001) than the CIA group. Among patients with non-TC (n=30), both groups had a similar ORR (55.0% vs. 60.0%, p=1.000) and PFS (233 days vs. 256.5 days, p=0.989). Discussion To the best of our knowledge, this study is the first to serially evaluate CIA/CINV and weight loss as well as their impact on therapeutic efficacy in patients with stage IV NSCLC. First, we observed a strong association between CIA and weight loss during treatment. Second, CIA was associated with a lower relative dose intensity. Finally, CIA was an unfavorable predictor of poor treatment outcomes (ORR and PFS), especially in patients with complete control of CINV. Since anorexia in the early phase of platinum-based chemotherapy combined with ICIs potentially affects therapeutic efficacy, these results indicate that active interventions for CIA may improve multiple treatment outcomes. Few studies have reported an association between CIA and weight loss. In a post-hoc analysis of phase Ⅱ trial of the combination antiemetics for patients with thoracic malignancies treated with cisplatin-based chemotherapy (trial registration number, UMIN000036383), Miyawaki et al. reported that anorexia during platinum-based chemotherapy was strongly associated with a decrease in skeletal muscle mass and BMI [17]. They also showed that TC of CINV did not prevent loss of skeletal muscle mass and BMI, indicating the importance of managing CIA. Moreover, regarding the impact of weight loss during the chemotherapy for advanced NSCLC, Kimura et al. reported a strong association between decreased survival and the presence of cancer cachexia (defined as a body weight loss >5 or >2 % in patients with a BMI of <20 kg/㎡) occurring before or during treatment (3, 6, and 12 months after chemotherapy initiation) [18]. They also observed that patients who developed cachexia after initiating chemotherapy often experienced severe anorexia (≥grade 3) during the first 3 months of chemotherapy. The present study and those by Miyawaki and Kimura demonstrate that CIA, but not CINV, is potentially associated with weight loss and shorter survival. Although CIA and CINV are mediated by some common molecules, such as histamine 1(H1), dopamine 2 (D2), and 5-hydroxytryptamine (5-HT) receptors, other aspects of CIA pathogenesis may involve molecules that differ from those of CINV. This is supported by the result in which 71.4% of patients in the CIA and non-TC groups overlapped in this study, but some were from different populations and had different clinical outcomes, particularly those with poor response to treatment in the CIA group. Therefore, a “CIA-focused” supportive care approach, distinct from antiemetic therapy, may be needed to improve clinical outcomes. Studies have identified several key molecules, including ghrelin and GDF-15, as significant in appetite and body weight regulation [17-20]. Exogenous ghrelin and anti-GDF-15 antibodies can potentially mitigate the adverse effects of chemotherapy, such as reduced food intake and weight loss [21]. However, the complexities of CIA extend beyond chemotherapy-induced nausea and vomiting and involve taste and oral mucosal disorders. Current treatments such as corticosteroids, gastroprokinetic agents, and rikkunshito have limited effectiveness [22-26]. Notably, recent trials have demonstrated that olanzapine improves appetite and weight gain in patients with advanced cancer, which has led to its recommendation in the American Society of Clinical Oncology (ASCO) cachexia guidelines [27]. Regarding the mechanisms that explain the association between CIA and chemotherapy efficacy, we observed a lower relative dose intensity in the CIA group than that in the non-CIA group. Crawford et al. reported that a relative dose intensity of <85% was associated with increased mortality in platinum-based chemotherapy for advanced NSCLC [19]. In addition, another study found that a relative dose intensity of <80% was associated with a decreased response rate and poor OS in patients aged ≥70 years [20]. Although the difference in relative dose intensity between the CIA and non-CIA groups in this study was significant, the difference was numerically very small and may not necessarily explain all differences in response rate, PFS, OS, and other treatment effects. In addition to dose intensity, there are suspected mechanisms and biomarkers common to both the appearance of CIA associated with chemotherapy and the favorable antitumor effect of chemotherapy. Ghrelin and GDF-15 are two molecules that may be associated with CIA. Anamorelin, an oral ghrelin agonist, has been shown to increase oral intake and muscle mass (body weight) but not to augment the therapeutic effects of chemotherapy [28]. In addition, basic research has shown that GDF-15 is associated with metastatic potential[29], proliferative capacity [30], therapeutic efficacy [31], and decreased survival [32, 33]. Moreover, anti-GDF-15 antibodies are also expected to potentiate the action of immune checkpoint inhibitors [31]. Future prospective studies evaluating anorexia, weight loss, and treatment efficacy, including biomarker studies, are required to further provide further clarity. This study showed that in the well-controlled CINV population (TC group), patients without CIA had a higher ORR and longer PFS than patients with CIA, although this difference was not statistically significant. In contrast, in the population with uncontrolled CINV (non-TC group), both patients with and without CIA had a similar ORR (55.0% vs. 60.0%, p=1.000) and PFS (233 days vs. 256.5 days, p=0.989). This indicates that in a population with well-controlled CINV, treatment should focus on the control of CIA. Olanzapine, recently added to the standard antiemetic regimen, was effective in randomized phase III trials for CIA and weight gain during chemotherapy [21]. The J-FORCE study highlighted the efficacy of olanzapine in highly emetogenic risk regimens including cisplatin, with a TC rate of 86% in the acute phase (-24 h) and 60% in the delayed phase (-120 h) [10]. In this study, the treatment regimen was not limited to cisplatin; carboplatin regimens accounted for 68.5% of patients, and the overall TC rate was high (71.7%). However, the frequency of olanzapine use, regardless of preventive use, was very low (22.6%). Further studies are needed to determine whether thorough olanzapine use improves CIA and its treatment efficacy. If molecules other than H1, D2, and 5-HT receptors, ghrelin and GDF-15, are implicated in both the development of CIA and a poor response to treatment, it would be intriguing to investigate whether the intensive use of olanzapine might, to some extent, improve CIA without necessarily improving treatment efficacy. Such an investigation could yield significant findings, including insights into the mechanisms underlying CIA and potential for more aggressive therapeutic strategies. This study has some limitations. First, this was a single-center retrospective analysis with a small sample size, which limits the generalizability and may introduce selection bias. Second, information on nausea, vomiting, and anorexia was not prospectively collected using patient-reported questionnaires, therefore mild cases of these symptoms may have been overlooked. Finally, the implementation of additional antiemetic therapy, such as olanzapine, relies on the judgment of the treating physician, and there is a need to consider the lack of standardized criteria for treatment intensification. Conclusion The results of this study show an association between CIA observed early in treatment, weight loss, and poor response to treatment in patients with NSCLC receiving platinum-based chemotherapy combined with ICI. These data indicate that aggressive supportive therapy for CIA may be required to prevent weight loss and to maintain therapeutic efficacy of platinum doublet chemotherapy plus ICIs. Future large-scale prospective studies are warranted to further assess and validate these results. Abbreviations 5-HT, 5-hydroxytryptamine; AUC, area under the blood concentration time curve; ASCO, American Society of Clinical Oncology; Bev, bevacizumab; BMI, body mass index; CBDCA, carboplatin; CDDP, cisplatin; CI, confidence interval; CIA, chemotherapy-induced anorexia; CINV, chemotherapy-induced nausea and vomiting; CTCAE, Common Terminology Criteria for Adverse Events; D2, dopamine 2; ECOG PS, Eastern Cooperative Oncology Group performance status; H1, histamine 1; HR, hazard ratio; ICI, immune checkpoint inhibitor; IQR, interquartile range; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; PD-L1, programmed cell death ligand 1; PEM, pemetrexed; PFS, progression-free survival; PS, performance status; PTX, paclitaxel; QOL, quality of life; RECIST, Response Evaluation Criteria in Solid Tumors; TC, total control; TPN, total parenteral nutrition TPN. Declarations Ethics approval and consent to participate All procedures performed in the human participant were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study was approved by the Institutional Review Board of Shizuoka Cancer Center. The Institutional Review Board of Shizuoka Cancer Center waived the requirement for patient consent because this was a retrospective study and anonymity was secured. Consent for publication Not applicable. Availability of data and materials The datasets used and analysed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding None. Authors’ contributions KD was a major contributor in conception and writing the manuscript. TN contributed conceptualization and writing. KD and TN contributed data curation and supervision. SM, MM, MS, KM, HK, MY, NM, YI, NM, HK, RK, KW, AO, HM, HK, and TT contributed substantively revised the work. All authors read and approved the final manuscript. Acknowledgements We thank Editage [http:// www. editage. com] for editing and reviewing this manuscript for the English language. References Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394-424. Martin L, Senesse P, Gioulbasanis I, Antoun S, Bozzetti F, Deans C, et al. Diagnostic criteria for the classification of cancer-associated weight loss. J Clin Oncol. 2015;33:90-9. Kadakia KC, Hamilton-Reeves JM, Baracos VE. Current therapeutic targets in cancer cachexia: A pathophysiologic approach. Am Soc Clin Oncol Educ Book. 2023;43:e389942. 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Poli‐Bigelli S, Rodrigues‐Pereira J, Carides AD, Julie Ma G, Eldridge K, Hipple A, et al. Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy‐induced nausea and vomiting. Results from a randomized, double-blind, placebo-controlled trial in Latin America. Cancer. 2003;97:3090-8. Hesketh PJ, Grunberg SM, Gralla RJ, Warr DG, Roila F, De Wit R, et al. The oral Neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: A multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin—The aprepitant Protocol 052 Study Group. J Clin Oncol. 2003;21:4112-9 Protocol 052. Hashimoto H, Abe M, Tokuyama O, Mizutani H, Uchitomi Y, Yamaguchi T, et al. Olanzapine 5 mg plus standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting (J-FORCE): A multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. 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Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205-16. Lorigan P, Woll PJ, O'Brien MER, Ashcroft LF, Sampson MR, Thatcher N. Randomized Phase III trial of dose-dense chemotherapy supported by whole-blood hematopoietic progenitors in better-prognosis small-cell lung cancer. J Natl Cancer Inst. 2005;97:666-74. Nakashima K, Murakami H, Yokoyama K, Omori S, Wakuda K, Ono A, et al. A Phase II study of palonosetron, aprepitant, dexamethasone and olanzapine for the prevention of cisplatin-based chemotherapy-induced nausea and vomiting in patients with thoracic malignancy. Jpn J Clin Oncol. 2017;47:840-3. Kimura M, Naito T, Kenmotsu H, Taira T, Wakuda K, Oyakawa T, et al. Prognostic impact of cancer cachexia in patients with advanced non-small cell lung cancer. Support Care Cancer. 2015;23:1699-708. Crawford J, Denduluri N, Patt D, Jiao X, Morrow PK, Garcia J, et al. Relative dose intensity of first-line chemotherapy and overall survival in patients with advanced non-small-cell lung cancer. Support Care Cancer. 2020;28:925-32. Luciani A, Bertuzzi C, Ascione G, Di Gennaro E, Bozzoni S, Zonato S, et al. Dose intensity correlate with survival in elderly patients treated with chemotherapy for advanced non-small cell lung cancer. Lung Cancer. 2009;66:94-6. Brunetto AT, Carden CP, Myerson J, Faria AL, Ashley S, Popat S, et al. Modest reductions in dose intensity and drug-induced neutropenia have no major impact on survival of patients with non-small cell lung cancer treated with platinum-doublet chemotherapy. J Thorac Oncol. 2010;5:1397-403. Matsuo N, Morita T, Matsuda Y, Okamoto K, Matsumoto Y, Kaneishi K, et al. Predictors of responses to corticosteroids for anorexia in advanced cancer patients: a multicenter prospective observational study. Supportive Care in Cancer. 2017;25(1):41-50. Ohno T, Yanai, Ando, Toyomasu, Ogawa, Morita, et al. Rikkunshito, a traditional Japanese medicine, suppresses cisplatin-induced anorexia in humans. Clinical and Experimental Gastroenterology. 2011:291. Harada T, Amano T, Ikari T, Takamura K, Ogi T, Fujikane T, et al. Rikkunshito for Preventing Chemotherapy-Induced Nausea and Vomiting in Lung Cancer Patients: Results from 2 Prospective, Randomized Phase 2 Trials. Front Pharmacol. 2017;8:972. Yoshiya T, Mimae T, Ito M, Sasada S, Tsutani Y, Satoh K, et al. Prospective, randomized, cross-over pilot study of the effects of Rikkunshito, a Japanese traditional herbal medicine, on anorexia and plasma-acylated ghrelin levels in lung cancer patients undergoing cisplatin-based chemotherapy. Investigational New Drugs. 2020;38(2):485-92. Ohnishi S, Watari H, Kanno M, Ohba Y, Takeuchi S, Miyaji T, et al. Additive effect of rikkunshito, an herbal medicine, on chemotherapy-induced nausea, vomiting, and anorexia in uterine cervical or corpus cancer patients treated with cisplatin and paclitaxel: results of a randomized phase II study (JORTC KMP-02). Journal of Gynecologic Oncology. 2017;28(5). Roeland EJ, Bohlke K, Baracos VE, Smith TJ, Loprinzi CL. Cancer Cachexia: ASCO Guideline Rapid Recommendation Update. J Clin Oncol. 2023;41(25):4178-9. Temel JS, Abernethy AP, Currow DC, Friend J, Duus EM, Yan Y, et al. Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomised, double-blind, phase 3 trials. The Lancet Oncology. 2016;17(4):519-31. Senapati S, Rachagani S, Chaudhary K, Johansson SL, Singh RK, Batra SK. Overexpression of macrophage inhibitory cytokine-1 induces metastasis of human prostate cancer cells through the FAK–RhoA signaling pathway. Oncogene. 2010;29(9):1293-302. Li S, Ma Y-M, Zheng P-S, Zhang P. GDF15 promotes the proliferation of cervical cancer cells by phosphorylating AKT1 and Erk1/2 through the receptor ErbB2. Journal of Experimental & Clinical Cancer Research. 2018;37(1). Haake M, Haack B, Schäfer T, Harter PN, Mattavelli G, Eiring P, et al. Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment. Nat Commun. 2023;14:4253. Liu YN, Wang XB, Wang T, Zhang C, Zhang KP, Zhi XY, et al. Macrophage Inhibitory Cytokine-1 as a Novel Diagnostic and Prognostic Biomarker in Stage I and II Nonsmall Cell Lung Cancer. Chin Med J (Engl). 2016;129(17):2026-32. Li C, Wang J, Kong J, Tang J, Wu Y, Xu E, et al. GDF15 promotes EMT and metastasis in colorectal cancer. Oncotarget. 2016;7(1):860-72. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4106256","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":283329828,"identity":"219fed8d-b574-4886-ac6f-52e8506334ae","order_by":0,"name":"Kosei Doshita","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Kosei","middleName":"","lastName":"Doshita","suffix":""},{"id":283329831,"identity":"e3a4e492-8ec6-41ad-966d-a8110bff5852","order_by":1,"name":"Tateaki 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08:44:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4106256/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4106256/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":53491240,"identity":"efca188d-8222-4537-9991-ded8799427e2","added_by":"auto","created_at":"2024-03-26 15:45:59","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":34294,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePatient selection diagram\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4106256/v1/5cbd251e96f3c3f8d627362e.png"},{"id":53491202,"identity":"b450798f-1559-4272-bbfa-8c3f3e948847","added_by":"auto","created_at":"2024-03-26 15:45:57","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":69985,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eBody weight and BMI change from baseline in each group\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePercentage of body weight change from baseline: (a) CIA group vs. non-CIA group (c) non-TC group vs. TC group. BMI change from baseline: (b) CIA group vs. non-CIA group (d) non-TC group vs. TC group. Mean changes ± standard errors for physical parameters from baseline value are shown.\u003c/p\u003e\n\u003cp\u003eThe p-value derived from the Wilcoxon signed-rank test is shown.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4106256/v1/521281dc84fedbefb2fca4cc.png"},{"id":53491198,"identity":"8bb4090e-f393-4c1f-b65a-0b8793b54989","added_by":"auto","created_at":"2024-03-26 15:45:54","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":66370,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan–Meier curves for progression-free survival (PFS) and overall survival (OS)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKaplan–Meier curves by arm for PFS using sub-group patients with CIA/non-CIA (a) and sub-group patients with non-TC/TC (b). Kaplan–Meier curves by arm for OS using sub-group patients with CIA/non-CIA (c) and sub-group patients with non-TC/TC (d).\u003c/p\u003e\n\u003cp\u003eThe numbers under the x-axis represent the numbers of patients at risk. P values are derived from log-rank tests for A–D.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4106256/v1/b1241158a5ec1ff1acafd1b3.png"},{"id":54765964,"identity":"ed8112ad-f572-48a1-9979-a2d9c0837557","added_by":"auto","created_at":"2024-04-16 12:55:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":660643,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4106256/v1/dd2eccb7-279d-4038-871c-49e255415e94.pdf"},{"id":53491201,"identity":"4d9b3138-46e6-4dbe-b452-eee8e4794679","added_by":"auto","created_at":"2024-03-26 15:45:57","extension":"pptx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":47148,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTableA1.pptx","url":"https://assets-eu.researchsquare.com/files/rs-4106256/v1/b1eca8e2f8bf056a4181c92b.pptx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Exploring the Relationship Between Anorexia and Therapeutic Efficacy in Advanced Lung Cancer Treatment: A Retrospective Study","fulltext":[{"header":"Background","content":"\u003cp\u003eLung cancer is the leading cause of cancer-related deaths worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Cancer-associated weight or skeletal muscle loss is commonly observed in patients with advanced lung cancer undergoing chemotherapy [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Cancer chemotherapy regimens frequently cause weight and skeletal muscle loss [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], partly due to chemotherapy-induced anorexia (CIA) or chemotherapy-induced nausea and vomiting (CINV), which are among the most unpleasant adverse events. However, there is no clear definition of CIA, which is characterized by early satiety or a decrease or loss of physiological desire to consume food. CIA is associated with the systemic impact of cancer-induced weight loss and results in worsening performance status (PS) and quality of life (QOL) [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In contrast to CINV, the assessment and management of CIA is currently not incorporated into the routine supportive care pathway for patients receiving platinum-based chemotherapy. Even with the implementation of standard antiemetic therapy for the control of CINV, complete response (CR; no vomiting, no use of rescue medication) and complete control (CC; CR\u0026thinsp;+\u0026thinsp;no significant nausea) rates ranged from 40\u0026ndash;75% [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. A randomized controlled phase III trial evaluating the efficacy of adding olanzapine to a triple-drug antiemetic regimen (the J-FORCE trial) reported a high incidence of anorexia (63.2%), despite a 79% CR for CINV in the olanzapine group [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn addition, CIA potentially affects oncologic outcomes of chemotherapy. Previous studies have reported that weight loss diminishes the therapeutic effects of immune checkpoint inhibitors (ICI) used either as monotherapy or in combination with platinum-based chemotherapy for the treatment of stage IV non-small cell lung cancer (NSCLC) [\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], and a correlation between anorexia and weight loss has been observed in the context of chemotherapy [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. To date, there have been no investigations on the relationship between CIA and weight loss during platinum-based chemotherapy combined with ICIs for stage IV NSCLC.\u003c/p\u003e \u003cp\u003eTherefore, the purpose of this study was to elucidate the incidence of CIA and the frequency of weight loss in patients with stage IV NSCLC receiving platinum-based chemotherapy combined with immune therapy and standard antiemetic therapy. In addition, this study also sought to determine whether CIA leads to weight loss and whether it is associated with treatment effectiveness.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and patients\u003c/h2\u003e \u003cp\u003eThis retrospective study included patients with stage IV NSCLC treated with first-line platinum-based chemotherapy combined with ICIs. We retrospectively reviewed the medical records of consecutive patients treated at Shizuoka Cancer Center between January 2019 and October 2022. Disease stage was determined according to the TNM classification (8th edition) proposed by the International Association for the Study of Lung Cancer [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. This retrospective study was approved by the Institutional Ethical Review Board of Shizuoka Cancer Center (J2023-105-2023-1). Patients were able to opt out of the study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eData collection and response evaluation\u003c/h2\u003e \u003cp\u003eThe following patient data at the start of first-line chemotherapy were obtained from medical records: age, sex, smoking status, Eastern Cooperative Oncology Group performance status (ECOG PS), histology, programmed cell death ligand 1(PD-L1) status, clinical stage, body weight (at the start of and 6 months before first-line chemotherapy), height, type of platinum agent, dose used in first-line chemotherapy, type of concomitant anticancer drug and dose used in first-line chemotherapy, type of immune checkpoint inhibitor, tumor response to first-line chemotherapy, duration from the start of platinum doublet chemotherapy to the last date of platinum doublet chemotherapy, treatment interval of each course, dose reduction, treatment cessation, dose delivery (defined as the effectively delivered chemotherapy dose considering all reductions and omissions) of each anticancer drug, date of death, or any recurrences detected with any imaging modality or the last visit. The best tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, version 1.1 [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eChemotherapy regimens\u003c/h2\u003e \u003cp\u003eThe patients received platinum-based chemotherapy combined with ICIs. The following platinum-based regimens were used: Cisplatin (CDDP) (75 mg/m\u003csup\u003e2\u003c/sup\u003e on day 1) and pemetrexed (PEM) (500 mg/m\u003csup\u003e2\u003c/sup\u003e on day 1); carboplatin (CBDCA) (area under the blood concentration time curve [AUC]\u0026thinsp;=\u0026thinsp;5 on day 1) and PEM (500 mg/m\u003csup\u003e2\u003c/sup\u003e on day 1); CBDCA (AUC\u0026thinsp;=\u0026thinsp;6 on day 1) and paclitaxel (PTX) (200 mg/m\u003csup\u003e2\u003c/sup\u003e on day 1); CBDCA (AUC\u0026thinsp;=\u0026thinsp;6 on day 1) and nab-PTX (100 mg/m\u003csup\u003e2\u003c/sup\u003e on day 1); or CBDCA (AUC\u0026thinsp;=\u0026thinsp;6 on day 1), PTX (200 mg/m\u003csup\u003e2\u003c/sup\u003e on day 1), and bevacizumab (Bev) (15 mg/m\u003csup\u003e2\u003c/sup\u003e on day 1) for up to four courses followed by either concomitant anticancer drugs or ICIs as maintenance therapy. Pembrolizumab was combined with CDDP, CBDCA\u0026thinsp;+\u0026thinsp;PEM, CBDCA\u0026thinsp;+\u0026thinsp;PTX or nab-PTX. Atezolizumab was administered with CBDCA\u0026thinsp;+\u0026thinsp;PEM, CBDCA\u0026thinsp;+\u0026thinsp;PTX, CBDCA\u0026thinsp;+\u0026thinsp;nab-PTX, and CBDCA\u0026thinsp;+\u0026thinsp;PTX\u0026thinsp;+\u0026thinsp;bevacizumab. Nivolumab and ipilimumab were administered with CBDCA\u0026thinsp;+\u0026thinsp;PEM. One-step dose reduction of the platinum agent and/or concomitant anticancer drug was performed for grade 4 hematologic toxicity, grade 3 febrile neutropenia, or grade 3 non-hematologic toxicity (except nausea, anorexia, hyponatremia, weight loss, alopecia, and constipation). Dose reduction was also allowed at the physician\u0026rsquo;s discretion.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eAntiemetic therapy\u003c/h2\u003e \u003cp\u003eThe enrolled patients received standard antiemetic therapy (palonosetron, aprepitant, and dexamethasone) and olanzapine on or after the administration of the first course of chemotherapy. Palonosetron was administered intravenously at a dose of 0.75 mg 30\u0026ndash;60 min before chemotherapy on day 1. Aprepitant was administered orally at a dose of 25 mg 60\u0026ndash;90 min before chemotherapy on day 1 and at a dose of 80 mg on days 2 and 3. Dexamethasone was administered intravenously at a dose of 9.9 mg 30\u0026ndash;60 min before chemotherapy on day 1 and then orally at a dose of 8 mg on days 2\u0026ndash;4. Olanzapine was administered orally at a dose of 5 mg once daily after dinner on days 1\u0026ndash;4 or 1\u0026ndash;5. The decision to administer olanzapine prophylactically from the initial treatment was based on the physician\u0026rsquo;s decision.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eAssessments\u003c/h2\u003e \u003cp\u003eNutritional assessment\u003c/p\u003e \u003cp\u003eBody weight (kg) was measured to the nearest 0.1 kg, and the body mass index (BMI) was subsequently calculated as body weight(kg)/[height (m)]\u003csup\u003e2\u003c/sup\u003e at baseline, 6 weeks, and 9 weeks after initiating chemotherapy.\u003c/p\u003e \u003cp\u003eAssessment of chemotherapy-induced nausea and vomiting\u003c/p\u003e \u003cp\u003eCINV was evaluated based on the proportion of patients who did not experience nausea or vomiting and did not require additional treatment with antiemetics. Doctors or nurses reported nausea and vomiting in electronic medical records using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 as follows:\u003c/p\u003e \u003cp\u003eNausea: grade 1, loss of appetite without alteration in eating habits; grade 2, decreased oral intake without significant weight loss, dehydration, or malnutrition; grade 3, inadequate oral caloric or fluid intake; tube feedings, total parenteral nutrition (TPN), or hospitalization indicated.\u003c/p\u003e \u003cp\u003eVomiting: grade 1, intervention not indicated; grade 2, outpatient intravenous hydration; medical intervention indicated; grade 3, tube feeding, TPN, or hospitalization indicated; grade 4, life-threatening consequences.\u003c/p\u003e \u003cp\u003eTotal control (TC) of CINV was defined as the absence of nausea and vomiting without additional treatment with antiemetics during the 0\u0026ndash;168 h period after the first course of chemotherapy. Patients were classified into the TC group if their CINV was completely controlled during the first course of chemotherapy; otherwise, they were classified into the non-TC group. In this study, we evaluated CINV for the first 168 h, which is longer than that reported previously. In previous reports on CINV and CIA during the first 5 days (120 h) after the start of treatment, control of CINV and CIA on day 5 was incomplete and gastrointestinal symptoms of CINV and CIA persisted after day 5 [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Therefore, in this study, the CINV/CIA observation period was set at 7 days (168 h) from the start of the treatment.\u003c/p\u003e \u003cp\u003eAssessment of chemotherapy-induced anorexia\u003c/p\u003e \u003cp\u003eCIA was defined as decreased appetite during the 0\u0026ndash;168 h period after the first course of chemotherapy. Doctors or nurses reported anorexia on electronic medical records using the CTCAE version 5.0 as follows: grade 1, loss of appetite without alteration in eating habits; grade 2, oral intake altered without significant weight loss or malnutrition with oral nutritional supplements indicated; grade 3, associated with significant weight loss or malnutrition (e.g., inadequate oral caloric and/or fluid intake) with tube feeding or TPN indicated; and grade 4, life-threatening consequences requiring urgent intervention.\u003c/p\u003e \u003cp\u003eBecause grade 2 or higher anorexia affects oral intake, patients were classified into the CIA group if their appetite loss worsened from anorexia grade 0\u0026ndash;1 to grade\u0026thinsp;\u0026ge;\u0026thinsp;2 during the 0\u0026ndash;168 h period following the initiation of chemotherapy, and patients were classified into the non-CIA group if they had no anorexia or their worst anorexia grade during the 0\u0026ndash;168 h period after chemotherapy initiation was 1.\u003c/p\u003e \u003cp\u003eAssessment of treatment delivery\u003c/p\u003e \u003cp\u003eThe median duration of chemotherapy was defined as the period from the first day of chemotherapy to the day of the last chemotherapy dose in the final cycle. The treatment interval was the date from the last chemotherapy dose in each course to the first day of the next course.\u003c/p\u003e \u003cp\u003eRelative dose intensity (total dose received over actual treatment duration divided by the total dose prescribed by the planned over the theoretical treatment period) was calculated as described by Lorigan et al. [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] Dose reduction was considered to have occurred if there was at least one dose reduction during the treatment period. Other events were collected if the interval between treatment cycles was more than 1 week longer than expected, or if treatment was stopped for reasons other than disease progression.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003eThe primary outcomes were changes in body weight and BMI. The secondary outcomes were dose delivery (relative dose intensity, incidence of dose reduction, or treatment delay or cessation), overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Patient characteristics were compared both descriptively and statistically using Fisher\u0026rsquo;s exact test for categorical variables and the Wilcoxon test for continuous variables. ORR was calculated as the complete plus partial response rate, which was measured using RECIST ver. 1.1. OS and PFS were measured as the intervals between the start of first-line chemotherapy and death, or any recurrence detected with any imaging modality or the last visit, respectively. Survival curves were plotted using the Kaplan\u0026ndash;Meier method and compared using standard log-rank tests. Data for patients without disease progression or who were lost to follow-up were censored at the last visit. A two-sided p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. JMP (ver. 14.0, SAS Institute) software was used for statistical analyses.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cem\u003ePatient characteristics\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eFrom January 2019 to October 2022, 110 patients with stage IV NSCLC were treated with combination therapy including an ICI and platinum doublet chemotherapy. Four patients were excluded from this study because of a lack of information on body weight at 6 and 9 weeks after the initiation of the first course of chemotherapy (Fig. 1). The median follow-up duration was 389 days (95% confidence interval [CI]: 319\u0026ndash;470 days).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe median age was 67.5 years, 81 (76.4%) were male, 105 (99.1%) had good PS (ECOG-PS 0\u0026ndash;1), and 94 (88.7%) were current or former smokers. The most common histological types were adenocarcinoma (n=82, 77.4%) and squamous cell carcinoma (n=14, 13.2%). Twenty-one (19.8%) patients had more than 5% body weight loss 6 months before the start of first-line chemotherapy. Patient characteristics at the start of the first-line chemotherapy are shown in Table 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1. Patient characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"636\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.739403453689167%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAll patient\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=106)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003enon-CIA\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=92)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.343799058084773%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCIA\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=14)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.361067503924646%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTC\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=76)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003enon-TC\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=30)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.832025117739404%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.739403453689167%\" valign=\"top\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e67.5\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(36\u0026ndash;85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e67.5\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(36\u0026ndash;85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.343799058084773%\" valign=\"top\"\u003e\n \u003cp\u003e66.5\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(57\u0026ndash;74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.361067503924646%\" valign=\"top\"\u003e\n \u003cp\u003e0.815\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e68\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(36\u0026ndash;85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e64.5\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(50\u0026ndash;83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.832025117739404%\" valign=\"top\"\u003e\n \u003cp\u003e0.277\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.739403453689167%\" valign=\"top\"\u003e\n \u003cp\u003eSex, n (%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Male\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e81 (76.4)\u003c/p\u003e\n \u003cp\u003e25 (23.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e69 (75.0)\u003c/p\u003e\n \u003cp\u003e23 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.343799058084773%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e12 (85.7)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;2 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.361067503924646%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.511\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e57 (75.0)\u003c/p\u003e\n \u003cp\u003e19 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e24 (80.0)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;6 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.832025117739404%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.799\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"8\" valign=\"top\"\u003e\n \u003cp\u003eECOG-PS, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.739403453689167%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;0\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;1\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e24 (22.6)\u003c/p\u003e\n \u003cp\u003e81 (76.4)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;1 (0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e23 (25.0)\u003c/p\u003e\n \u003cp\u003e68 (73.9)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;1 (1.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.343799058084773%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;1 (7.1)\u003c/p\u003e\n \u003cp\u003e13 (92.9)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.361067503924646%\" valign=\"top\"\u003e\n \u003cp\u003e0.290\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e20 (26.3)\u003c/p\u003e\n \u003cp\u003e55 (72.4)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;1 (1.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;4 (13.3)\u003c/p\u003e\n \u003cp\u003e26 (86.7)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.832025117739404%\" valign=\"top\"\u003e\n \u003cp\u003e0.314\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"8\" valign=\"top\"\u003e\n \u003cp\u003eHistopathology, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.739403453689167%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Ad\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Sq\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Other\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e82 (77.4)\u003c/p\u003e\n \u003cp\u003e14 (13.2)\u003c/p\u003e\n \u003cp\u003e10 (9.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e73 (79.4)\u003c/p\u003e\n \u003cp\u003e11 (12.0)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;8 (8.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.343799058084773%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;9 (64.3)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;3 (21.4)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;2 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.361067503924646%\" valign=\"top\"\u003e\n \u003cp\u003e0.184\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e60 (79.0)\u003c/p\u003e\n \u003cp\u003e11 (14.5)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;5 (6.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e22 (73.3)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;3 (10.0)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;5 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.832025117739404%\" valign=\"top\"\u003e\n \u003cp\u003e0.281\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"8\" valign=\"top\"\u003e\n \u003cp\u003ePD-L1 status, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.739403453689167%\" valign=\"top\"\u003e\n \u003cp\u003e \u0026nbsp;\u0026ge;50%\u003c/p\u003e\n \u003cp\u003e1-49%\u003c/p\u003e\n \u003cp\u003e \u0026nbsp;\u0026lt;1%\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eunknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e11 (10.4)\u003c/p\u003e\n \u003cp\u003e31 (29.2)\u003c/p\u003e\n \u003cp\u003e59 (55.7)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;5 (4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e10 (10.9)\u003c/p\u003e\n \u003cp\u003e26 (28.3)\u003c/p\u003e\n \u003cp\u003e51 (55.4)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;5 (5.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.343799058084773%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;1 (7.1)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;5 (35.7)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;8 (57.1)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.361067503924646%\" valign=\"top\"\u003e\n \u003cp\u003e0.959\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e10 (13.2)\u003c/p\u003e\n \u003cp\u003e21 (27.6)\u003c/p\u003e\n \u003cp\u003e40 (52.6)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;5 (6.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;1 (3.3)\u003c/p\u003e\n \u003cp\u003e10 (33.3)\u003c/p\u003e\n \u003cp\u003e19 (63.3)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.832025117739404%\" valign=\"top\"\u003e\n \u003cp\u003e0.236\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.739403453689167%\" valign=\"top\"\u003e\n \u003cp\u003eStage, n (%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;ⅣA\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;ⅣB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e51 (48.1)\u003c/p\u003e\n \u003cp\u003e55 (51.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e45 (48.9)\u003c/p\u003e\n \u003cp\u003e47 (51.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.343799058084773%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;6 (42.9)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;8 (57.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.361067503924646%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.778\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e40 (52.6)\u003c/p\u003e\n \u003cp\u003e36 (47.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e11 (36.7)\u003c/p\u003e\n \u003cp\u003e19 (63.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.832025117739404%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.195\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"8\" valign=\"top\"\u003e\n \u003cp\u003eSmoking status, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.739403453689167%\" valign=\"top\"\u003e\n \u003cp\u003eCurrent/former\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Never\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e94 (88.7)\u003c/p\u003e\n \u003cp\u003e12 (11.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e81 (88.0)\u003c/p\u003e\n \u003cp\u003e11 (12.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.343799058084773%\" valign=\"top\"\u003e\n \u003cp\u003e13 (92.9)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;1 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.361067503924646%\" valign=\"top\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e67 (88.2)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;9 (11.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e27 (90.0)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;3 (10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.832025117739404%\" valign=\"top\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.739403453689167%\" valign=\"top\"\u003e\n \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e21.2\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(15.7\u0026ndash;35.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e21.7\u003c/p\u003e\n \u003cp\u003e(15.7\u0026ndash;33.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.343799058084773%\" valign=\"top\"\u003e\n \u003cp\u003e19.6\u003c/p\u003e\n \u003cp\u003e(17.4\u0026ndash;35.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.361067503924646%\" valign=\"top\"\u003e\n \u003cp\u003e0.334\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e21.5\u003c/p\u003e\n \u003cp\u003e(15.7\u0026ndash;35.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e20.6\u003c/p\u003e\n \u003cp\u003e(16.4\u0026ndash;26.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.832025117739404%\" valign=\"top\"\u003e\n \u003cp\u003e0.285\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"8\" valign=\"top\"\u003e\n \u003cp\u003e\u0026ge;5％\u0026nbsp;Body weight loss in previous 6 months\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.739403453689167%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Yes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;No\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Unknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e21 (19.8)\u003c/p\u003e\n \u003cp\u003e40 (37.7)\u003c/p\u003e\n \u003cp\u003e45 (42.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e16 (17.4)\u003c/p\u003e\n \u003cp\u003e35 (38.0)\u003c/p\u003e\n \u003cp\u003e41 (44.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.343799058084773%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;5 (35.7)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;5 (35.7)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;4 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.361067503924646%\" valign=\"top\"\u003e\n \u003cp\u003e0.271\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e15 (19.7)\u003c/p\u003e\n \u003cp\u003e30 (39.5)\u003c/p\u003e\n \u003cp\u003e31 (40.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;6 (20.0)\u003c/p\u003e\n \u003cp\u003e10 (33.3)\u003c/p\u003e\n \u003cp\u003e14 (46.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.832025117739404%\" valign=\"top\"\u003e\n \u003cp\u003e0.818\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.739403453689167%\" valign=\"top\"\u003e\n \u003cp\u003ePlatinum agent\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;CDDP\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;CBDCA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e30 (34.0)\u003c/p\u003e\n \u003cp\u003e76 (66.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e29 (31.5)\u003c/p\u003e\n \u003cp\u003e63 (68.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.343799058084773%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;7 (50.0)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;7 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.361067503924646%\" valign=\"top\"\u003e\n \u003cp\u003e0.227\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e24 (31.6)\u003c/p\u003e\n \u003cp\u003e52 (68.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e12 (40.0\u003c/p\u003e\n \u003cp\u003e18 (60.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.832025117739404%\" valign=\"top\"\u003e\n \u003cp\u003e0.496\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"8\" valign=\"top\"\u003e\n \u003cp\u003eConcomitant anticancer drug, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.739403453689167%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;PEM\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;nab-PTX\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;PTX\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;PTX+Bev\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e81 (76.4)\u003c/p\u003e\n \u003cp\u003e14 (13.2)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;5 (4.7)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;6 (5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e73 (79.4)\u003c/p\u003e\n \u003cp\u003e11 (12.0)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;4 (4.4)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;4 (4.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.343799058084773%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;8 (57.1)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;3 (21.4)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;1 (7.1)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;2 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.361067503924646%\" valign=\"top\"\u003e\n \u003cp\u003e0.119\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e58 (76.3)\u003c/p\u003e\n \u003cp\u003e10 (13.2)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;4 (5.3)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;4 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e23 (76.7)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;4 (13.3)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;1 (3.3)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;2 (6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.832025117739404%\" valign=\"top\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"8\" valign=\"top\"\u003e\n \u003cp\u003eConcomitant Immune checkpoint inhibitor, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.739403453689167%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Pembrolizumab\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Atezolizumab\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Nivo+Ipi\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e89 (84.0)\u003c/p\u003e\n \u003cp\u003e16 (15.1)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;1 (0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e78 (84.8)\u003c/p\u003e\n \u003cp\u003e13 (14.1)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;1 (1.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.343799058084773%\" valign=\"top\"\u003e\n \u003cp\u003e11 (78.6)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;3 (21.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.361067503924646%\" valign=\"top\"\u003e\n \u003cp\u003e0.518\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e64 (84.2)\u003c/p\u003e\n \u003cp\u003e11 (14.5)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;1 (1.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e25 (80.0)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;5 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.832025117739404%\" valign=\"top\"\u003e\n \u003cp\u003e0.836\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"8\" valign=\"top\"\u003e\n \u003cp\u003eUse of Olanzapine on days 1\u0026ndash;8 of the first course of treatment, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.739403453689167%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Yes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;No\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Preventive use\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e24 (22.6)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e82 (77.4)\u003c/p\u003e\n \u003cp\u003e18 (17.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e18 (19.6)\u003c/p\u003e\n \u003cp\u003e74 (80.4)\u003c/p\u003e\n \u003cp\u003e16 (17.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.343799058084773%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;6 (42.9)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;8 (57.1)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;2 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.361067503924646%\" valign=\"top\"\u003e\n \u003cp\u003e0.081\u003c/p\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e12 (15.8)\u003c/p\u003e\n \u003cp\u003e64 (84.2)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;6 (7.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.930926216640502%\" valign=\"top\"\u003e\n \u003cp\u003e12 (40.0)\u003c/p\u003e\n \u003cp\u003e18 (60.0)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;6 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.832025117739404%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.011\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e0.579\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviation: ECOG-PS, Eastern Cooperative Oncology Group Performance; Ad, adenocarcinoma; Sq, squamous cell carcinoma; PD-L1, programmed cell death ligand 1; BMI, body mass index; CDDP, cisplatin; CBDCA, carboplatin; PEM, pemetrexed; PTX, paclitaxel; Bev, bevacizumab; Nivo, nivolumab; Ipi, ipilimumab.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFrequency of CINV and CIA\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Among the 106 patients, 14 (13.2%) and 30 (28.3%) were classified into the CIA and non-TC groups, respectively. Of these, 10 in the CIA group (10/14, 71.4%) were in the non-TC group and 10 in the non-TC group (10/30, 33.3%) were in the CIA group (Pearson\u0026apos;s chi-square test, p=0.0001) (Supplementary Table A1). There were no significant between-group differences in clinicopathological characteristics, such as age, sex, ECOG-PS, tumor histology, PD-L1 status, clinical stage, smoking status, baseline BMI, frequency of body weight loss \u0026ge; 5% in the previous 6 months, and drugs used (platinum agents, concomitant anticancer drugs, and ICIs). The use of olanzapine on days 1\u0026ndash;8 of the first course of treatment was not significantly different between the CIA and non-CIA groups, but was more frequent in the non-TC than in the TC group. There was no significant group difference in the preventive use of olanzapine.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDose delivery and therapy duration\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThere were no significant differences in the type of platinum agent used (CDDP use: CIA, 7 [50.0%] vs. non-CIA, 29 [31.5%]; p=0.23); non-TC, 12 [40.0%] vs. TC, 24 [31.6%]; p=0.50), mean duration of platinum doublet chemotherapy, treatment interval per course, or cycles of platinum doublet chemotherapy.\u003c/p\u003e\n\u003cp\u003eThere was no difference in the median number of cycles for platinum doublet chemotherapy administration: 4 (range: 3\u0026ndash;4) in the CIA group, 4 (range: 4\u0026ndash;4) in the non-CIA group (p=0.80), 4 (range: 4\u0026ndash;4) in the non-TC group, and 4 (range: 3\u0026ndash;4) in the TC group (p=0.34). The median number of cycles for maintenance therapy administration was significantly lower in the CIA than in the non-CIA group (5, range: 3\u0026ndash;6 vs. 8, range: 5\u0026ndash;15; p=0.01), but not in the non-TC and TC groups (4, range: 4\u0026ndash;4 vs. 4, range: 3\u0026ndash;4; p=0.34).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe relative dose delivery intensity of platinum agents and combination anticancer drugs was 100% in the CIA (interquartile range [IQR]: 100\u0026ndash;100) and non-CIA groups (IQR: 87.5\u0026ndash;100), and that of concomitant anticancer drugs was 100% in the CIA (IQR: 100\u0026ndash;100) and non-CIA groups (IQR: 85.9\u0026ndash;100). Notably, both were significantly lower in the CIA group (p\u0026lt;0.01). In addition, the frequency of dose reduction within the first four cycles for platinum agents and concomitant anticancer drugs was significantly higher in the CIA group than in the non-CIA group (platinum agent: 2.2% vs. 28.6%, p\u0026lt;0.01; concomitant anticancer drugs: 4.4% vs. 28.6%, p=0.01). No significant differences in the frequency of dose reduction were observed between the TC and non-TC groups (platinum agent: 4.0% vs. 10.0%, p=0.35. concomitant anticancer drugs: 5.3% vs. 13.3%, p=0.22). There was no significant between-group difference in the frequency of dose delays of \u0026ge;1 week or treatment cessation (Table 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2. Dose intensity by CIA/TC group\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"723\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.60027662517289%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003enon-CIA\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=92)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.926694329183956%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCIA\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=14)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.298755186721992%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTC\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=76)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003enon-TC\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=30)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.298755186721992%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.60027662517289%\" valign=\"top\"\u003e\n \u003cp\u003eConcomitant platinum-agent, n (%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; CDDP\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; CBDCA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e29 (31.5)\u003c/p\u003e\n \u003cp\u003e63 (68.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.926694329183956%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7 (50.0)\u003c/p\u003e\n \u003cp\u003e7 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.298755186721992%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e24 (31.6)\u003c/p\u003e\n \u003cp\u003e52 (68.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e12 (40.0)\u003c/p\u003e\n \u003cp\u003e18 (60.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.298755186721992%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.50\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.60027662517289%\" valign=\"top\"\u003e\n \u003cp\u003eMean duration of platinum-doublet therapy [weeks]\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e9.7\u003c/p\u003e\n \u003cp\u003e(9\u0026ndash;11.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.926694329183956%\" valign=\"top\"\u003e\n \u003cp\u003e9.9\u003c/p\u003e\n \u003cp\u003e(8.9\u0026ndash;12.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.298755186721992%\" valign=\"top\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e9.1\u003c/p\u003e\n \u003cp\u003e(9\u0026ndash;11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e10.1\u003c/p\u003e\n \u003cp\u003e(9.2\u0026ndash;12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.298755186721992%\" valign=\"top\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.60027662517289%\" valign=\"top\"\u003e\n \u003cp\u003eTreatment interval / course (days)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e23.3\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(21\u0026ndash;27.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.926694329183956%\" valign=\"top\"\u003e\n \u003cp\u003e23.0\u003c/p\u003e\n \u003cp\u003e(21.3\u0026ndash;28.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.298755186721992%\" valign=\"top\"\u003e\n \u003cp\u003e0.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e22.8\u003c/p\u003e\n \u003cp\u003e(21\u0026ndash;27.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e23.5\u003c/p\u003e\n \u003cp\u003e(21.3\u0026ndash;28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.298755186721992%\" valign=\"top\"\u003e\n \u003cp\u003e0.42\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.60027662517289%\" valign=\"top\"\u003e\n \u003cp\u003eCycles for platinum-doublet therapy\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e(4\u0026ndash;4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.926694329183956%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e(3\u0026ndash;4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.298755186721992%\" valign=\"top\"\u003e\n \u003cp\u003e0.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e(4\u0026ndash;4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e(4\u0026ndash;4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.298755186721992%\" valign=\"top\"\u003e\n \u003cp\u003e0.34\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.60027662517289%\" valign=\"top\"\u003e\n \u003cp\u003eCycles for maintenance therapy\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003cp\u003e(5\u0026ndash;15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.926694329183956%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e(3\u0026ndash;6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.298755186721992%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.01\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003cp\u003e(4\u0026ndash;15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003cp\u003e(5\u0026ndash;10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.298755186721992%\" valign=\"top\"\u003e\n \u003cp\u003e0.25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.60027662517289%\" valign=\"top\"\u003e\n \u003cp\u003ePlatinum-agent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"10.926694329183956%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.298755186721992%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.298755186721992%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.60027662517289%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Relative dose intensity (%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003cp\u003e(100\u0026ndash;100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.926694329183956%\" valign=\"top\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003cp\u003e(87.5\u0026ndash;100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.298755186721992%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.01\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003cp\u003e(100\u0026ndash;100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003cp\u003e(100\u0026ndash;100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.298755186721992%\" valign=\"top\"\u003e\n \u003cp\u003e0.22\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.60027662517289%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Dose reduction\u003csup\u003ea\u003c/sup\u003e [within 4 cycles], n (%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e2 (2.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.926694329183956%\" valign=\"top\"\u003e\n \u003cp\u003e4 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.298755186721992%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.01\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e3 (4.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e3 (10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.298755186721992%\" valign=\"top\"\u003e\n \u003cp\u003e0.35\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.60027662517289%\" valign=\"top\"\u003e\n \u003cp\u003eCombination anticancer drug\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"10.926694329183956%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.298755186721992%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.298755186721992%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.60027662517289%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Relative dose intensity (%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003cp\u003e(100\u0026ndash;100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.926694329183956%\" valign=\"top\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003cp\u003e(85.9\u0026ndash;100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.298755186721992%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.01\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003cp\u003e(100\u0026ndash;100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003cp\u003e(100\u0026ndash;100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.298755186721992%\" valign=\"top\"\u003e\n \u003cp\u003e0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.60027662517289%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Dose reduction\u003csup\u003eb\u003c/sup\u003e [within 4 cycles], n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e4 (4.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.926694329183956%\" valign=\"top\"\u003e\n \u003cp\u003e4 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.298755186721992%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.01\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e4 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e4 (13.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.298755186721992%\" valign=\"top\"\u003e\n \u003cp\u003e0.22\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.60027662517289%\" valign=\"top\"\u003e\n \u003cp\u003eDose delays \u0026ge;1 week / cycle \u0026nbsp;[within 4 cycles], n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e47\u0026nbsp;(51.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.926694329183956%\" valign=\"top\"\u003e\n \u003cp\u003e5 (35.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.298755186721992%\" valign=\"top\"\u003e\n \u003cp\u003e0.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e36 (47.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e16 (53.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.298755186721992%\" valign=\"top\"\u003e\n \u003cp\u003e0.67\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.60027662517289%\" valign=\"top\"\u003e\n \u003cp\u003eTreatment cessation [not PD, within 4 cycles], n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e12 (13.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.926694329183956%\" valign=\"top\"\u003e\n \u003cp\u003e3 (21.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.298755186721992%\" valign=\"top\"\u003e\n \u003cp\u003e0.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e11 (14.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.95850622406639%\" valign=\"top\"\u003e\n \u003cp\u003e4 (13.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.298755186721992%\" valign=\"top\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eReasons for dose reductions: Grade 3 anorexia (3), Grade 3 febrile neutropenia (2), and Grade 2 rash (1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003eReasons for dose reductions: Grade 3 anorexia (3), Grade 3 febrile neutropenia (2), \u0026nbsp; Grade 2 rash (2), and Grade 2 peripheral sensory neuropathy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eImpact of CIA and CINV on body weight and BMI\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe change in weight from baseline was significantly different between the CIA and non-CIA groups 6 and 9 weeks after treatment initiation (6 weeks: -4.28% vs. 0.36%, p=0.012; 9 weeks: -2.90% vs. 2.20%, p=0.007) (Fig. 2a), but not between the non-TC and TC groups (6 weeks: 0.39% vs. 0.34%, p=0.988; 9 weeks: 2.66 vs. 1.71, p=0.492) (Fig. 2b).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe change in BMI from baseline was also significantly different between the CIA and non-CIA groups 6 and 9 weeks after treatment initiation (6 weeks: -0.79 vs. 0.07, p=0.011; -0.56 vs. 0.45; p=0.011) (Fig. 2c), but not between the non-TC and TC groups (6 weeks: 0.07 vs. 0.07, p=0.994; 9 weeks: 0.47 vs. 0.40, p=0.627) (Fig. 2d, Table 3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Body weight and BM\u003c/strong\u003e\u003cstrong\u003eI\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"662\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.54984894259819%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.83987915407855%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003enon-CIA\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=92)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.83987915407855%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCIA\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=14)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.818731117824774%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.141993957703928%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTC\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=76)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.83987915407855%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003enon-TC\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=30)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.969788519637461%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"7\" valign=\"top\"\u003e\n \u003cp\u003eChange in weight from baseline (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.54984894259819%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; 6 weeks after treatment initiation\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(IQR)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; (missing value=2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.83987915407855%\" valign=\"top\"\u003e\n \u003cp\u003e0.36\u003c/p\u003e\n \u003cp\u003e(-1.75\u0026ndash;2.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.83987915407855%\" valign=\"top\"\u003e\n \u003cp\u003e-4.28\u003c/p\u003e\n \u003cp\u003e(-8.89\u0026ndash;0.47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.818731117824774%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.012\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.141993957703928%\" valign=\"top\"\u003e\n \u003cp\u003e0.34\u003c/p\u003e\n \u003cp\u003e(-2.56\u0026ndash;2.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.83987915407855%\" valign=\"top\"\u003e\n \u003cp\u003e0.39\u003c/p\u003e\n \u003cp\u003e(-3.02\u0026ndash;2.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.969788519637461%\" valign=\"top\"\u003e\n \u003cp\u003e0.988\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.54984894259819%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; 9 weeks after treatment initiation\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(IQR)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; (missing value=4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.83987915407855%\" valign=\"top\"\u003e\n \u003cp\u003e2.20\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-1.14\u0026ndash;4.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.83987915407855%\" valign=\"top\"\u003e\n \u003cp\u003e-2.90\u003c/p\u003e\n \u003cp\u003e(-11.0\u0026ndash;3.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.818731117824774%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.007\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.141993957703928%\" valign=\"top\"\u003e\n \u003cp\u003e1.71\u003c/p\u003e\n \u003cp\u003e(-2.30\u0026ndash;3.64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.83987915407855%\" valign=\"top\"\u003e\n \u003cp\u003e2.66\u003c/p\u003e\n \u003cp\u003e(-1.85\u0026ndash;4.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.969788519637461%\" valign=\"top\"\u003e\n \u003cp\u003e0.492\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"7\" valign=\"top\"\u003e\n \u003cp\u003eChange in BMI from baseline (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.54984894259819%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; 6 weeks after treatment initiation\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.83987915407855%\" valign=\"top\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003cp\u003e(-0.40\u0026ndash;0.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.83987915407855%\" valign=\"top\"\u003e\n \u003cp\u003e-0.79\u003c/p\u003e\n \u003cp\u003e(-1.93\u0026ndash;0.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.818731117824774%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.011\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.141993957703928%\" valign=\"top\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003cp\u003e(-0.57\u0026ndash;0.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.83987915407855%\" valign=\"top\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003cp\u003e(-0.61\u0026ndash;0.47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.969788519637461%\" valign=\"top\"\u003e\n \u003cp\u003e0.994\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.54984894259819%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; 9 weeks after treatment initiation\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.83987915407855%\" valign=\"top\"\u003e\n \u003cp\u003e0.45\u003c/p\u003e\n \u003cp\u003e(-0.23\u0026ndash;0.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.83987915407855%\" valign=\"top\"\u003e\n \u003cp\u003e-0.56\u003c/p\u003e\n \u003cp\u003e(-2.27\u0026ndash;0.64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.818731117824774%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.007\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.141993957703928%\" valign=\"top\"\u003e\n \u003cp\u003e0.40\u003c/p\u003e\n \u003cp\u003e(-0.55\u0026ndash;0.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.83987915407855%\" valign=\"top\"\u003e\n \u003cp\u003e0.47\u003c/p\u003e\n \u003cp\u003e(-0.38\u0026ndash;0.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.969788519637461%\" valign=\"top\"\u003e\n \u003cp\u003e0.627\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: BMI, body mass index; CIA, chemotherapy-induced anorexia; IQR, interquartile range; TC, total control.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEfficacy\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAt the time of data cutoff (October 20, 2023), the median follow-up duration from the start of first-line chemotherapy for censored cases was 389 days (95% CI: 319\u0026ndash;470 days). Of the 106 included patients, 36 (34.0%) had died at the time of the data cutoff. For the entire cohort, the median PFS was 236.5 days (95% CI: 176\u0026ndash;290 days). Although the non-CIA group showed better PFS than the CIA group (median PFS: 258.5 days vs. 123.5 days, HR: 0.57, 95% CI: 0.31\u0026ndash;1.03, p=0.06; Fig. 3a), the difference was not statistically significant. There was no significant difference in PFS between the TC and non-TC groups (median PFS: 236.5 days vs. 237 days; HR, 0.70; 95% CI: 0.45\u0026ndash;1.10, p=0.12; Fig. 3b).\u003c/p\u003e\n\u003cp\u003eOS was also better in the non-CIA group than in the CIA group (median OS: 640 vs. 394.5 days, HR: 0.67, 95% CI: 0.35\u0026ndash;1.29, p=0.23; Fig. 3c), however, the difference was not statistically significant. In addition, there was no significant difference in OS between the TC and non-TC groups (median OS, 458 vs. 610 days; HR, 0.97; 95% CI: 0.58\u0026ndash;1.63, p=0.91; Fig. 3d).\u003c/p\u003e\n\u003cp\u003eThe ORR and PFS stratified according to CIA/non-CIA and TC/non-TC groups are shown in Supplementary Table A1. Among patients with TC (n=76), the non-CIA group had a higher ORR (48.6% vs. 25.0, p=0.617), although the difference was not statistically significant, and longer PFS (262 days vs. 91 days, p\u0026lt;0.0001) than the CIA group. Among patients with non-TC (n=30), both groups had a similar ORR (55.0% vs. 60.0%, p=1.000) and PFS (233 days vs. 256.5 days, p=0.989).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo the best of our knowledge, this study is the first to serially evaluate CIA/CINV and weight loss as well as their impact on therapeutic efficacy in patients with stage IV NSCLC. First, we observed a strong association between CIA and weight loss during treatment. Second, CIA was associated with a lower relative dose intensity. Finally, CIA was an unfavorable predictor of poor treatment outcomes (ORR and PFS), especially in patients with complete control of CINV. Since anorexia in the early phase of platinum-based chemotherapy combined with ICIs potentially affects therapeutic efficacy, these results indicate that active interventions for CIA may improve multiple treatment outcomes.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFew studies have reported an association between CIA and weight loss. In a post-hoc analysis of phase Ⅱ trial of the combination antiemetics for patients with thoracic malignancies treated with cisplatin-based chemotherapy (trial registration number, UMIN000036383), Miyawaki et al. \u0026nbsp;reported that anorexia during platinum-based chemotherapy was strongly associated with a decrease in skeletal muscle mass and BMI [17]. They also showed that TC of CINV did not prevent loss of skeletal muscle mass and BMI, indicating the importance of managing CIA. Moreover, regarding the impact of weight loss during the chemotherapy for advanced NSCLC, Kimura et al. reported a strong association between decreased survival and the presence of cancer cachexia (defined as a body weight loss \u0026gt;5 or \u0026gt;2 % in patients with a BMI of \u0026lt;20 kg/㎡) occurring before or during treatment (3, 6, and 12 months after chemotherapy initiation) [18]. They also observed that patients who developed cachexia after initiating chemotherapy often experienced severe anorexia (\u0026ge;grade 3) during the first 3 months of chemotherapy. The present study and those by Miyawaki and Kimura demonstrate that CIA, but not CINV, is potentially associated with weight loss and shorter survival.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAlthough CIA and CINV are mediated by some common molecules, such as histamine 1(H1), dopamine 2 (D2), and 5-hydroxytryptamine (5-HT) receptors, other aspects of CIA pathogenesis may involve molecules that differ from those of CINV. This is supported by the result in which 71.4% of patients in the CIA and non-TC groups overlapped in this study, but some were from different populations and had different clinical outcomes, particularly those with poor response to treatment in the CIA group. Therefore, a \u0026ldquo;CIA-focused\u0026rdquo; supportive care approach, distinct from antiemetic therapy, may be needed to improve clinical outcomes. Studies have identified several key molecules, including ghrelin and GDF-15, as significant in appetite and body weight regulation [17-20]. Exogenous ghrelin and anti-GDF-15 antibodies can potentially mitigate the adverse effects of chemotherapy, such as reduced food intake and weight loss [21]. However, the complexities of CIA extend beyond chemotherapy-induced nausea and vomiting and involve taste and oral mucosal disorders. Current treatments such as corticosteroids, gastroprokinetic agents, and rikkunshito have limited effectiveness [22-26]. Notably, recent trials have demonstrated that olanzapine improves appetite and weight gain in patients with advanced cancer, which has led to its recommendation in the American Society of Clinical Oncology (ASCO) cachexia guidelines [27].\u003c/p\u003e\n\u003cp\u003eRegarding the mechanisms that explain the association between CIA and chemotherapy efficacy, we observed a lower relative dose intensity in the CIA group than that in the non-CIA group. Crawford et al. reported that a relative dose intensity of \u0026lt;85% was associated with increased mortality in platinum-based chemotherapy for advanced NSCLC\u0026nbsp;[19]. In addition, another study found that a relative dose intensity of \u0026lt;80% was associated with a decreased response rate and poor OS in patients aged \u0026ge;70 years\u0026nbsp;[20]. Although the difference in relative dose intensity between the CIA and non-CIA groups in this study was significant, the difference was numerically very small and may not necessarily explain all differences in response rate, PFS, OS, and other treatment effects. In addition to dose intensity, there are suspected mechanisms and biomarkers common to both the appearance of CIA associated with chemotherapy and the favorable antitumor effect of chemotherapy. Ghrelin and GDF-15 are two molecules that may be associated with CIA. Anamorelin, an oral ghrelin agonist, has been shown to increase oral intake and muscle mass (body weight) but not to augment the therapeutic effects of chemotherapy [28]. In addition, basic research has shown that GDF-15 is associated with metastatic potential[29], proliferative capacity [30], therapeutic efficacy [31], and decreased survival [32, 33]. Moreover, anti-GDF-15 antibodies are also expected to potentiate the action of immune checkpoint inhibitors\u0026nbsp;[31]. Future prospective studies evaluating anorexia, weight loss, and treatment efficacy, including biomarker studies, are required to further provide further clarity.\u003c/p\u003e\n\u003cp\u003eThis study showed that in the well-controlled CINV population (TC group), patients without CIA had a higher ORR and longer PFS than patients with CIA, although this difference was not statistically significant. In contrast, in the population with uncontrolled CINV (non-TC group), both patients with and without CIA had a similar ORR (55.0% vs. 60.0%, p=1.000) and PFS (233 days vs. 256.5 days, p=0.989). This indicates that in a population with well-controlled CINV, treatment should focus on the control of CIA. Olanzapine, recently added to the standard antiemetic regimen, was effective in randomized phase III trials for CIA and weight gain during chemotherapy\u0026nbsp;[21]. The J-FORCE study highlighted the efficacy of olanzapine in highly emetogenic risk regimens including cisplatin, with a TC rate of 86% in the acute phase (-24 h) and 60% in the delayed phase (-120 h) [10]. In this study, the treatment regimen was not limited to cisplatin; carboplatin regimens accounted for 68.5% of patients, and the overall TC rate was high (71.7%). However, the frequency of olanzapine use, regardless of preventive use, was very low (22.6%). Further studies are needed to determine whether thorough olanzapine use improves CIA and its treatment efficacy. If molecules other than H1, D2, and 5-HT receptors, ghrelin and GDF-15, are implicated in both the development of CIA and a poor response to treatment, it would be intriguing to investigate whether the intensive use of olanzapine might, to some extent, improve CIA without necessarily improving treatment efficacy. Such an investigation could yield significant findings, including insights into the mechanisms underlying CIA and potential for more aggressive therapeutic strategies.\u003c/p\u003e\n\u003cp\u003e This study has some limitations. First, this was a single-center retrospective analysis with a small sample size, which limits the generalizability and may introduce selection bias. Second, information on nausea, vomiting, and anorexia was not prospectively collected using patient-reported questionnaires, therefore mild cases of these symptoms may have been overlooked. Finally, the implementation of additional antiemetic therapy, such as olanzapine, relies on the judgment of the treating physician, and there is a need to consider the lack of standardized criteria for treatment intensification.\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe results of this study show an association between CIA observed early in treatment, weight loss, and poor response to treatment in patients with NSCLC receiving platinum-based chemotherapy combined with ICI. These data indicate that aggressive supportive therapy for CIA may be required to prevent weight loss and to maintain therapeutic efficacy of platinum doublet chemotherapy plus ICIs. Future large-scale prospective studies are warranted to further assess and validate these results.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e5-HT, 5-hydroxytryptamine; AUC, area under the blood concentration time curve; ASCO, American Society of Clinical Oncology; Bev, bevacizumab; BMI, body mass index; CBDCA, carboplatin; CDDP, cisplatin; CI, confidence interval; CIA, chemotherapy-induced anorexia; CINV, chemotherapy-induced nausea and vomiting; CTCAE, Common Terminology Criteria for Adverse Events; D2, dopamine 2; ECOG PS, Eastern Cooperative Oncology Group performance status; H1, histamine 1; HR, hazard ratio; ICI, immune checkpoint inhibitor; IQR, interquartile range; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; PD-L1, programmed cell death ligand 1; PEM, pemetrexed; PFS, progression-free survival; PS, performance status; PTX, paclitaxel; QOL, quality of life; RECIST, Response Evaluation Criteria in Solid Tumors; TC, total control; TPN, total parenteral nutrition TPN.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAll procedures performed in the human participant were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study was approved by the Institutional Review Board of Shizuoka Cancer Center. The Institutional Review Board of Shizuoka Cancer Center waived the requirement for patient consent because this was a retrospective study and anonymity was secured.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAvailability of data and materials\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAuthors\u0026rsquo; contributions\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eKD was a major contributor in conception and writing the manuscript. TN contributed conceptualization and writing. KD and TN contributed data curation and supervision. SM, MM, MS, KM, HK, MY, NM, YI, NM, HK, RK, KW, AO, HM, HK, and TT contributed substantively revised the work. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAcknowledgements\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Editage [http:// www. editage. com] for editing and reviewing this manuscript for the English language.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394-424.\u003c/li\u003e\n\u003cli\u003eMartin L, Senesse P, Gioulbasanis I, Antoun S, Bozzetti F, Deans C, et al. Diagnostic criteria for the classification of cancer-associated weight loss. 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Oncotarget. 2016;7(1):860-72.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Chemotherapy-induced anorexia, immune checkpoint inhibitors, non-small cell lung cancer, platinum-based chemotherapy, treatment efficacy","lastPublishedDoi":"10.21203/rs.3.rs-4106256/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4106256/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eChemotherapy-induced anorexia is frequently observed in patients with advanced lung cancer who are receiving chemotherapy. This study explored the relationship between chemotherapy-induced anorexia and therapeutic outcomes in patients with stage IV non-small cell lung cancer undergoing platinum-based chemotherapy combined with immune checkpoint inhibitors.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe retrospectively reviewed the medical records of 106 patients with stage IV non-small cell lung cancer treated with platinum-based chemotherapy combined with immune checkpoint inhibitors between January 2019 and October 2022. The incidence of weight loss and its association with treatment efficacy was assessed in the chemotherapy-induced anorexia group. Chemotherapy-induced anorexia and chemotherapy-induced nausea and vomiting were evaluated using Common Terminology Criteria for Adverse Events version 5.0. Progression-free and overall survival were used to measure treatment efficacy.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eChemotherapy-induced anorexia was observed in 13.2% of patients. Patients with chemotherapy-induced anorexia showed significant weight loss at 6 and 9 weeks after treatment initiation compared to those in the non-chemotherapy-induced anorexia group. Progression-free and overall survival were shorter in the chemotherapy-induced anorexia group than in the non-chemotherapy-induced anorexia group, but the difference was not statistically significant.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eChemotherapy-induced anorexia was associated with significant weight loss and reduced treatment efficacy in patients with stage IV non-small cell lung cancer. These findings suggest the need for aggressive supportive therapy for chemotherapy-induced anorexia to prevent weight loss and maintain therapeutic efficacy during platinum-based chemotherapy combined with immune checkpoint inhibitors.\u003c/p\u003e","manuscriptTitle":"Exploring the Relationship Between Anorexia and Therapeutic Efficacy in Advanced Lung Cancer Treatment: A Retrospective Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-26 15:45:38","doi":"10.21203/rs.3.rs-4106256/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3376cc57-245a-4033-94e8-01cf35b6258f","owner":[],"postedDate":"March 26th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-04-16T12:47:37+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-26 15:45:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4106256","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4106256","identity":"rs-4106256","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}