
==== Front
Thorac Cancer
Thorac Cancer
10.1111/(ISSN)1759-7714
TCA
Thoracic Cancer
1759-7706
1759-7714
John Wiley & Sons Australia, Ltd Melbourne

39075850
10.1111/1759-7714.15403
TCA15403
Original Article
Original Article
Exploring the relationship between anorexia and therapeutic efficacy in advanced lung cancer treatment: a retrospective study
Doshita et al.
Doshita Kosei https://orcid.org/0000-0002-0475-573X
1
Naito Tateaki https://orcid.org/0000-0003-4047-2929
1 t.naito@scchr.jp

Matsuda Suguru 1
Morita Meiko https://orcid.org/0009-0000-9248-4265
1
Sekikawa Motoki https://orcid.org/0009-0005-5637-5199
1
Miura Keita 1
Kodama Hiroaki https://orcid.org/0000-0002-0953-3183
1
Yabe Michitoshi 1
Morikawa Noboru 1
Iida Yuko https://orcid.org/0000-0002-1807-7781
1
Mamesaya Nobuaki 1
Kobayashi Haruki 1
Ko Ryo 1
Wakuda Kazushige 1
Ono Akira 1
Murakami Haruyasu https://orcid.org/0000-0003-2416-546X
1
Kenmotsu Hirotsugu 1
Takahashi Toshiaki https://orcid.org/0000-0002-8188-2505
1
1 Division of Thoracic Oncology Shizuoka Cancer Center Shizuoka Japan
* Correspondence
Tateaki Naito, Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi‐cho, Sunto‐gun, Shizuoka, 411‐8777, Japan.
Email: t.naito@scchr.jp

29 7 2024
9 2024
15 25 10.1111/tca.v15.25 18311841
22 6 2024
28 5 2024
26 6 2024
© 2024 The Author(s). Thoracic Cancer published by John Wiley & Sons Australia, Ltd.
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

Abstract

Background

Chemotherapy‐induced anorexia is a common occurrence in patients undergoing treatment for advanced lung cancer. However, the relationship between chemotherapy‐induced anorexia and weight loss during platinum‐based chemotherapy combined with immune checkpoint inhibitors is unclear. 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

The study retrospectively reviewed the medical records of 106 patients with stage IV non‐small‐cell lung cancer treated with platinum‐based chemotherapy and 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, nausea, and vomiting were evaluated using Common Terminology Criteria for Adverse Events v 5.0. Progression‐free and overall survival were used to measure treatment efficacy.

Results

Chemotherapy‐induced anorexia was observed in 13.2% of patients. These patients exhibited 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 results highlight the importance of implementing robust supportive care for chemotherapy‐induced anorexia to mitigate weight loss and uphold treatment effectiveness during platinum‐based chemotherapy combined with immune checkpoint inhibitors.

This retrospective 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. Chemotherapy‐induced anorexia was observed in 13.2% of patients, who exhibited 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, but the difference was not statistically significant. These findings underscore the importance of implementing robust supportive care for chemotherapy‐induced anorexia to mitigate weight loss and uphold treatment effectiveness.

anorexia
chemotherapy
immune checkpoint inhibitors
non‐small cell lung cancer
treatment efficacy
source-schema-version-number2.0
cover-dateSeptember 2024
details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.4.8 mode:remove_FC converted:02.09.2024
Doshita K , Naito T , Matsuda S , Morita M , Sekikawa M , Miura K , et al. Exploring the relationship between anorexia and therapeutic efficacy in advanced lung cancer treatment: a retrospective study. Thorac Cancer. 2024;15 (25 ):1831–1841. 10.1111/1759-7714.15403
==== Body
pmcINTRODUCTION

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 also 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. 4 , 5 , 6 In contrast to CINV, assessing and managing CIA are currently not incorporated into the routine supportive care pathway for patients receiving platinum‐based chemotherapy. Complete response (CR; no vomiting, no use of rescue medication) and control (CR + no significant nausea) rates ranged from 40% to 75%, even after implementing standard antiemetic therapy to control CINV. 7 , 8 , 9 Despite a 79% CR for CINV in the olanzapine group, a randomized controlled phase III trial evaluating the efficacy of adding olanzapine to a triple‐drug antiemetic regimen (J‐FORCE trial) reported a high incidence of anorexia (63.2%). 10

CIA also potentially affects the oncologic outcomes of chemotherapy. Weight loss diminishes the therapeutic effects of immune checkpoint inhibitors (ICIs) used as monotherapy or combined with platinum‐based chemotherapy for treating stage IV non‐small‐cell lung cancer (NSCLC). 11 , 12 , 13 Furthermore, a correlation between anorexia and weight loss has been observed in the context of chemotherapy. 4 However, no studies have investigated the relationship between CIA and weight loss during platinum‐based chemotherapy combined with ICIs for stage IV NSCLC.

This study aimed 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, the study also determined whether CIA leads to weight loss and whether it is associated with treatment effectiveness.

METHODS

Study design and patients

This retrospective study was approved by the Institutional Ethical Review Board of Shizuoka Cancer Center (approval no. J2023‐105‐2023‐1). Patients were able to opt out of the study at any time. The study included patients with stage IV NSCLC treated with first‐line platinum‐based chemotherapy combined with ICIs. The medical records of consecutive patients treated at Shizuoka Cancer Center between January 2019 and October 2022 were reviewed. The disease stage was determined according to the TNM classification (eighth edition) proposed by the International Association for the Study of Lung Cancer. 14

Data collection and response evaluation

The following patient data were obtained from medical records at the start of first‐line chemotherapy: 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, platinum agent type, dose used in first‐line chemotherapy, concomitant anticancer drug type 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 (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, v 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/m2 on day 1) and pemetrexed (PEM; 500 mg/m2 on day 1); carboplatin (CBDCA; area under the blood concentration–time curve [AUC] = 5 on day 1) and PEM (500 mg/m2 on day 1); CBDCA (AUC = 6 on day 1) and paclitaxel (PTX; 200 mg/m2 on day 1); CBDCA (AUC = 6 on day 1) and nab‐PTX (100 mg/m2 on day 1); or CBDCA (AUC = 6 on day 1), PTX (200 mg/m2 on day 1), and bevacizumab (Bev; 15 mg/m2 on day 1) for up to four courses followed by 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, a concomitant anticancer drug, or both were 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 allowed at the physician's discretion.

Antiemetic therapy

The patients received standard antiemetic therapy (palonosetron, aprepitant, and dexamethasone) and olanzapine on or after administering 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 125 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 between 7pm and 8 pm. on days 1–4 or 1–5. The physician decided whether to administer olanzapine prophylactically from the initial treatment.

Assessments

Nutritional assessment

Body weight (kg) was measured to the nearest 0.1 kg, and the body mass index (BMI) was 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) v 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.

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. This study evaluated CINV for the first 168 h, which is longer than that reported previously. CINV and CIA control on day 5 was incomplete, and gastrointestinal symptoms of CINV and CIA persisted after day 5 in previous reports on CINV and CIA during the first 5 days (120 h) after the start of treatment. 10 Therefore, the CINV/CIA observation period was 7 days (168 h) from the start of the treatment in this study.

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 CTCAE v 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, significant weight loss or malnutrition (e.g., inadequate oral caloric 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 after initiating chemotherapy. 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 treatment duration/total dose prescribed over the theoretical treatment period) was calculated as previously described. 16 Dose reduction occurred if there was at least one dose reduction during the treatment period. Other events were collected if the interval between treatment cycles was >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 descriptively and statistically compared 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 v 1.1. OS and PFS were determined 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 software (v 14.0, SAS Institute) 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 first chemotherapy course initiation (Figure 1). The median follow‐up duration was 389 days (95% confidence interval [CI] 319–470 days). Patient characteristics at the start of the first‐line chemotherapy are shown in Table 1.

FIGURE 1 Patient selection diagram. NSCLC, non‐small‐cell lung cancer.

TABLE 1 Patient characteristics.

	All patients (n = 106)	Non‐CIA (n = 92)	CIA (n = 14)	p value	TC (n = 76)	Non‐TC (n = 30)	p value	
Age (years)	67.5	67.5	66.5	0.815	68	64.5	0.277	
Median (range)	(36–85)	(36–85)	(57–74)		(36–85)	(50–83)		
Sex, n (%)								
Male	81 (76.4)	69 (75.0)	12 (85.7)	0.511	57 (75.0)	24 (80.0)	0.799	
Female	25 (23.6)	23 (25.0)	2 (14.3)		19 (25.0)	6 (20.0)		
ECOG‐PS, n (%)								
0	24 (22.6)	23 (25.0)	1 (7.1)	0.290	20 (26.3)	4 (13.3)	0.314	
1	81 (76.4)	68 (73.9)	13 (92.9)		55 (72.4)	26 (86.7)		
2	1 (0.9)	1 (1.1)	0 (0.0)		1 (1.3)	0 (0.0)		
Histopathology, n (%)								
Ad	82 (77.4)	73 (79.4)	9 (64.3)	0.184	60 (79.0)	22 (73.3)	0.281	
Sq	14 (13.2)	11 (12.0)	3 (21.4)		11 (14.5)	3 (10.0)		
Other	10 (9.4)	8 (8.7)	2 (14.3)		5 (6.6)	5 (16.7)		
PD‐L1 status, n (%)								
≥50%	11 (10.4)	10 (10.9)	1 (7.1)	0.959	10 (13.2)	1 (3.3)	0.236	
1–49%	31 (29.2)	26 (28.3)	5 (35.7)		21 (27.6)	10 (33.3)		
<1%	59 (55.7)	51 (55.4)	8 (57.1)		40 (52.6)	19 (63.3)		
Unknown	5 (4.7)	5 (5.4)	0 (0.0)		5 (6.6)	0 (0.0)		
Stage, n (%)								
IVA	51 (48.1)	45 (48.9)	6 (42.9)	0.778	40 (52.6)	11 (36.7)	0.195	
IVB	55 (51.9)	47 (51.1)	8 (57.1)		36 (47.4)	19 (63.3)		
Smoking status, n (%)								
Current/former	94 (88.7)	81 (88.0)	13 (92.9)	1.000	67 (88.2)	27 (90.0)	1.000	
Never	12 (11.3)	11 (12.0)	1 (7.1)		9 (11.8)	3 (10.0)		
BMI (kg/m2)	21.2	21.7	19.6	0.334	21.5	20.6	0.285	
Median (range)	(15.7–35.3)	(15.7–33.9)	(17.4–35.3)		(15.7–35.3)	(16.4–26.3)		
≥5% body weight loss in previous 6 months								
Yes	21 (19.8)	16 (17.4)	5 (35.7)	0.271	15 (19.7)	6 (20.0)	0.818	
No	40 (37.7)	35 (38.0)	5 (35.7)		30 (39.5)	10 (33.3)		
Unknown	45 (42.5)	41 (44.6)	4 (28.6)		31 (40.8)	14 (46.7)		
Platinum agent	30 (34.0)	29 (31.5)	7 (50.0)	0.227	24 (31.6)	12 (40.0	0.496	
CDDP	76 (66.0)	63 (68.5)	7 (50.0)		52 (68.4)	18 (60.0)		
CBDCA								
Concomitant anticancer drug, n (%)								
PEM	81 (76.4)	73 (79.4)	8 (57.1)	0.119	58 (76.3)	23 (76.7)	1.000	
nab‐PTX	14 (13.2)	11 (12.0)	3 (21.4)		10 (13.2)	4 (13.3)		
PTX	5 (4.7)	4 (4.4)	1 (7.1)		4 (5.3)	1 (3.3)		
PTX + Bev	6 (5.7)	4 (4.4)	2 (14.3)		4 (5.3)	2 (6.7)		
Concomitant Immune checkpoint inhibitor, n (%)								
Pembrolizumab	89 (84.0)	78 (84.8)	11 (78.6)	0.518	64 (84.2)	25 (80.0)	0.836	
Atezolizumab	16 (15.1)	13 (14.1)	3 (21.4)		11 (14.5)	5 (20.0)		
Nivo + Ipi	1 (0.9)	1 (1.1)			1 (1.3)			
Use of olanzapine on days 1–8 of the first course of treatment, n (%)								
Yes	24 (22.6)	18 (19.6)	6 (42.9)	0.081	12 (15.8)	12 (40.0)	0.011	
No	82 (77.4)	74 (80.4)	8 (57.1)	1.000	64 (84.2)	18 (60.0)	0.579	
Preventive use	18 (17.0)	16 (17.4)	2 (14.3)		6 (7.9)	6 (20.0)		
Abbreviations: Ad, adenocarcinoma; Bev, bevacizumab; BMI, body mass index; CBDCA, carboplatin; CDDP, cisplatin; ECOG‐PS, Eastern Cooperative Oncology Group Performance; Ipi, ipilimumab; Nivo, nivolumab; PD‐L1, programmed cell death ligand 1; PEM, pemetrexed; PTX, paclitaxel; Sq, squamous cell carcinoma.

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. Ten patients in the CIA group (71.4%) were in the non‐TC group, and 10 in the non‐TC group (33.3%) were in the CIA group (Pearson's chi‐square test, p = 0.0001) (Table A1). No significant between‐group differences were observed 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). Using olanzapine on days 1–8 of the first treatment course did not differ significantly between the CIA and non‐CIA groups but was more frequent in the non‐TC than in the TC group. No significant group differences were observed in the preventive use of olanzapine.

Dose delivery and therapy duration

No significant differences in the type of platinum agent used were observed (p = 0.50), mean duration of platinum doublet chemotherapy, treatment interval per course, or platinum doublet chemotherapy cycles.

No difference was observed in the median number of cycles for platinum doublet chemotherapy administration: four (range 3–4) in the CIA group, four (range 4–4) in the non‐CIA group (p = 0.80), four (range 4–4) in the non‐TC group, and four (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 (five, range 3–6 vs. eight, range 5–15; p = 0.01) but not in the non‐TC and TC groups (four, range 4–4 vs. four, range 3–4; p = 0.34).

The relative dose delivery intensity of platinum agents and combination anticancer drugs was 100% in the CIA group, and that of concomitant anticancer drugs was 100% in the CIA and non‐CIA groups. Notably, both were significantly lower in the CIA group than in the non‐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 were observed in the frequency of dose reduction 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). No significant between‐group difference was observed 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	29 (31.5)	7 (50.0)	0.23	24 (31.6)	12 (40.0)	0.50	
CBDCA	63 (68.5)	7 (50.0)		52 (68.4)	18 (60.0)		
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 (3, 4)	0.80	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	
Abbreviations: CBDCA, carboplatin; CDDP, cisplatin; CIA, chemotherapy‐induced anorexia; IQR, interquartile range; PD, progressive disease; TC, total control.

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 the baseline differed significantly 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) (Figure 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) (Figure 2b).

FIGURE 2 Body weight and body mass index (BMI) change from baseline in each group. Percentage of body weight change from the baseline: (a) CIA group vs. non‐CIA group and (c) non‐TC group vs. TC group. BMI change from baseline: (b) CIA group vs. non‐CIA group and (d) non‐TC group vs. TC group. Mean changes ± standard errors for physical parameters from the baseline value are shown. The p value derived from the Wilcoxon signed‐rank test is shown. CIA, chemotherapy‐induced anorexia; TC, total control.

The change in BMI from the baseline also differed significantly between the CIA and non‐CIA groups 6 and 9 weeks after treatment initiation (6 weeks −0.79 vs. 0.07, p = 0.011; 9 weeks −0.56 vs. 0.45; p = 0.011) (Figure 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) (Figure 2d, Table 3).

TABLE 3 Body weight and BMI.

	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/m2)							
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 patients, 36 (34.0%) had died at the time of the data cutoff. The median PFS was 236.5 days for the entire cohort (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, Hazard ratio [HR] 0.57, 95% CI 0.31–1.03, p = 0.06; Figure 3a), the difference was not statistically significant. No significant difference was observed 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; Figure 3b).

FIGURE 3 Kaplan–Meier curves for progression‐free survival (PFS) and overall survival (OS). Kaplan–Meier curves by arm for PFS using subgroup patients with CIA or non‐CIA (a) and subgroup patients with non‐TC or TC (b). Kaplan–Meier curves by arm for OS using subgroup patients with CIA/non‐CIA (c) and subgroup patients with non‐TC/TC (d). The numbers under the x axis represent the number of patients at risk. p values are derived from log‐rank tests for (a–d). CI, confidence interval; CIA, chemotherapy‐induced anorexia; HR, hazard ratio; mPFS, median progression free survival; TC, total control.

The 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; Figure 3c); however, the difference was not statistically significant. In addition, no significant difference was observed in the 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; Figure 3d).

The ORR and PFS stratified according to CIA/non‐CIA and TC/non‐TC groups are shown in Table A1. Among patients with TC (n = 76), the non‐CIA group had a higher ORR than the CIA group (51.3% vs. 25.0%, p = 0.617), but the difference was not statistically significant, and longer PFS (262 days vs. 91 days, p < 0.0001). Both patient groups with non‐TC (n = 30) had a similar ORR (55.0% vs. 60.0%, p = 1.000) and PFS (233 days vs. 256.5 days, p = 0.989).

DISCUSSION

This study is the first to serially evaluate CIA/CINV and weight loss, and their impact on therapeutic efficacy in patients with stage IV NSCLC. A strong association was observed between CIA and weight loss during treatment, and CIA was associated with a lower relative dose intensity. CIA was also an unfavorable predictor of poor treatment outcomes, especially in patients with complete CINV control. Because 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. Anorexia during platinum‐based chemotherapy was strongly associated with a decrease in skeletal muscle mass and BMI in a post hoc analysis of a phase II trial investigating combination antiemetics for patients with thoracic malignancies treated with cisplatin‐based chemotherapy (trial registration number, UMIN000036383). 17 Furthermore, TC of CINV did not prevent skeletal muscle mass loss and BMI, indicating the importance of managing CIA. Moreover, 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/m 2 ) was reported before or during treatment (3, 6, and 12 months after chemotherapy initiation). 18 Patients who developed cachexia after chemotherapy initiation also often experienced severe anorexia (≥ grade 3) during the first 3 months of chemotherapy. The present and previous studies demonstrate that CIA, but not CINV, is potentially associated with weight loss and shorter patient 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 different from those of CINV. This finding is supported by the result in which 71.4% of patients in the CIA and non‐TC groups overlapped in this study; however, some patients 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. Ghrelin and GDF‐15 are key molecules involved in appetite and body weight regulation. 17 , 18 , 19 , 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 also involve taste and oral mucosal disorders. Furthermore, current treatments such as corticosteroids, gastroprokinetic agents, and rikkunshito have limited effectiveness. 22 , 23 , 24 , 25 , 26 However, olanzapine improves appetite and weight gain in patients with advanced cancer, which has led to its recommendation in the American Society of Clinical Oncology cachexia guidelines. 27

Regarding the mechanisms that explain the association between CIA and chemotherapy efficacy, a lower relative dose intensity in the CIA group was observed than 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, 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 small and may not explain all differences in response rate, PFS, OS, and other treatment effects. In addition to dose intensity, some mechanisms and biomarkers are common to 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, increases oral intake and muscle mass (body weight) but does not augment the therapeutic effects of chemotherapy. 28 In addition, GDF‐15 is associated with metastatic potential, 29 proliferative capacity, 30 therapeutic efficacy 31 and decreased survival. 32 , 33 Anti‐GDF‐15 antibodies can also potentiate the action of immune checkpoint inhibitors. 31 However, future prospective studies evaluating anorexia, weight loss, and treatment efficacy, including biomarker studies, are required to provide further clarity.

This study showed a suboptimal ORR and PFS within the population effectively managing CINV (TC group), particularly in patients who developed CIA. The prognosis varied significantly between individuals with and without CIA, suggesting that CIA could influence oncologic outcomes. Consequently, developing proactive, supportive care that specifically addresses CIA and CINV management in patients with NSCLC receiving platinum‐based chemotherapy combined with ICI is crucial.

Olanzapine—which was 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 contrast, 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 71.7%. However, the frequency of olanzapine use, regardless of preventive use, was low (22.6%), therefore further studies are needed to determine whether thorough olanzapine use improves CIA and its treatment efficacy. Exploring the potential involvement of additional molecules beyond H1, D2, and 5‐HT receptors, ghrelin, and GDF‐15 in chemotherapy‐induced anorexia (CIA) development and poor treatment response warrants investigation, therefore investigating whether intensive use of olanzapine could partially alleviate chemotherapy‐induced anorexia (CIA) without necessarily enhancing treatment efficacy would be beneficial. Such an investigation could yield remarkable findings, including insights into the mechanisms underlying CIA and the 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. CIA and CINV occurrences were collected retrospectively from medical records, therefore there may have been omissions. The CIA group included more patients with PS 0, adenocarcinoma, and PD‐L1 ≥50%, although not significantly, which could have affected the PFS or OS. 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, implementing additional antiemetic therapy, such as olanzapine, relies on the judgment of the treating physician, and the lack of standardized criteria for treatment intensification must be addressed.

CONCLUSIONS

This study shows an association between CIA early in treatment, weight loss, and poor response to treatment in patients with NSCLC receiving platinum‐based chemotherapy combined with ICI, therefore aggressive supportive therapy for CIA is required to prevent weight loss and maintain the therapeutic efficacy of platinum doublet chemotherapy plus ICIs. Future large‐scale prospective studies are required to further assess and validate these results.

AUTHOR CONTRIBUTIONS

Conceptualization: K.D. and T.N. Writing—original draft: K.D. and T.N. Data curation: K.D. and T.N. Supervision: K.D. and T.N. Writing—review and editing: S.M., M.M., M.S., K.M., H.K., M.Y., N.M., Y.I., N.M., H.K., R.K., K.W., A.O., H.M., H.K., and T.T. All authors read and approved the final manuscript.

CONFLICT OF INTEREST STATEMENT

The authors declare that they have no competing interests.

Supporting information

Supporting Information Data S1 Supporting Information.

ACKNOWLEDGMENTS

We thank Editage (http://www.editage.com) for editing and reviewing this manuscript for English language.

DATA AVAILABILITY STATEMENT

The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.
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