1. Introduction

2. Materials and Methods

3. Results

3.2. Study Characteristics

The study characteristics reveal that among the 30 studies examined (Table 1AB), the majority of studies had observational cohort study designs (n = 24 for prospective study design [7,31,32,33,34,36,37,38,39,40,41,42,44,45,46,47,48,51,52,53,54,57,58,59], n = 5 for retrospective study design [35,43,49,55,56], while one study used a randomized control trial (RCT) [50].) Among 24 prospective studies, six studies [31,42,47,51,54,57] used longitudinal follow-up assessing chemotoxicity from baseline to after chemotherapy with multiple time points (at every cycle over 8 cycles [47,54]; at every 3 months over one year [51]; at every cycle over 12 cycles [31]; at weekly over a month [42]; at monthly over 3 months [57]) over the course of chemotherapy. The most common time point to assess chemotherapy was 6 months follow-up [7,35,39,49,50] throughout chemotherapy. None of the studies assessed chemotoxicity longer than 1 year follow-up. Studies were conducted across various countries, predominantly in Europe (studies n = 15 [7,32,33,34,35,36,39,40,41,48,50,51,52,53,54,59]), followed by Asia (studies n = 6 [45,47,49,55,57,58]) and United States (US) (studies n = 4 [37,38,43,44]). The sample sizes ranged from 2,691 [40] to 52 [33], and the sample sizes were between > 100 and < 500 in the majority of studies (n = 16). Among 30 studies, 24 studies [7,31,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,53,55,57] identified significant risk factors of chemotoxicity; 10 studies [31,33,37,39,40,43,46,48,49,50] examined the differences of chemotoxicity by categorical groups (i.e., high, versus low values) of risk factors; 11 studies reported odds ratios [ORs] [34,35,36,38,41,44,45,47,51,53,55,57]; and 2 studies [7,42] reported a Beta coefficient to present the associations of risk factors with chemotoxicity. Two studies found no significant risk factors of chemotoxicity [54,59], and four did not examine chemotoxicity risk factors [32,52,56,58].

Table 1. A. Characteristics of Studies Included for Meta-Analysis (N = 25).

Table 1. A. Characteristics of Studies Included for Meta-Analysis (N = 25).

Authors(year)/ Country	Study Design	Cancer types		Samples(N)/F(%)/ Mean Age [range]	Primary Regimens	Top 2 prevalence of moderate-to-severe chemotoxicity subgroupsa
Ali et al. (2016) /Canada& France	PL	CRC/ mixed stages		138/F50%/62[28–87]	5-FU	GI (20%)/Neuropathy (13%)
Antonio et al. (2018)/Europe	P	Older Adults CRC/ mixed stages		193/F32%/80[75–89]	5-FU	Diarrhea (9.5%)/ Fatigue, Neutropenia (8.1%)
Aparicio et al (2016)/Europe	P		Older Adults mCRC/IV	271/F42%/80[75–92]	5-FU	Neutropenia (22%)/ GI (20.8%)
Backshall et al. (2011)/Europe	P		mCRC/IV	52/F35%/79[42–86]	Cape	Hand-foot-syndrome (11%)/ Diarrhea (9%)
Barret et al. (2011)/Europe	P		mCRC/IV	114/F32%/65[22–92]	5-FU	Neuropathy (85.5%)/ GI (28.7%)
Beukers et al. (2021)/Europe	R		Older Adults Colon/III	97/F52%/77[70–85]	5-FU	Diarrhea (30%)/ Hand-foot syndrome (20%)
Breton et al. (2021)/Europe	P		mCRC/IV	2,190/F38%/67[59–75]	5-FU	Composite GI (15%)/ Neutropenia (13.2%)
Feliu et al. (2022)/Europe	P		Older Adults CRC/mixed stages	321/F32%/78[70–90]	5-FU	Fatigue (12%)/ Diarrhea (10%)
Folprecht et al. (2008)/Europe	P		CRC/ mixed stages	2,691/F33%/ 70[18–79]	5-FU	Neutropenia (28.9%)/ Diarrhea (20.5%)
Gallois et al. (2019)/Europe	P		Older Adults mCRC/IV	168/F44%/75[70–92]	5-FU	Nausea, vomiting (15%)/ Diarrhea (8%)
Garg et al. (2012)/Australia	PL		CRC/III	173/F43%/63[54–72]	5-FU	Neutropenia (55%)/ GI (50.6%, mucositis 12%)
Hochster et al. (2007)/USA	P		Older Adults CRC/ mixed stages	55/F47%/81[75–90]	Leucovorin	GI (35.7%)/ Diarrhea (25%)
Jung et al. (2015)/S.Korea	P		Colon/III	229/F59%/61[53–67]	5-FU	Neutropenia (40%)
Karabulut et al. (2022)/Turkey	P		mCRC/IV	137/F61%/62[18–83]	5-FU	Anemia (30%)/ GI (15.5%)
Li et al. (2021)/China	PL		CRC/no data	233/F34%/58[28–87]	Cape	Nausea (35%)/Vomiting (35%)
Okada et al. (2017)/Japan	R		mCRC/IV	108/F56%/65[34–83]	5-FU	Non-hematological (57%)/ Hematological toxicity (45%)
Osterlund et al. (2007)/Europe	RCT		mCRC/IV	150/F49%/60[31–75]	5-FU	GI (51%)/ Neutropenia (16%)
Retornaz et al. (2020)/Europe	PL		Older Adults Colon/ mixed stages	97/F51%/79[70–90]	5-FU	Fatigue (64%)/ GI (40%)
Sastre et al. (2012)/Europe	P		Older Adults mCRC/IV	66/F42%/70[70–86]	5-FU	Neuropathy (16%)/ Diarrhea (16%)
Seymour et al. (2011)/Europe	P		mCRC/IV	440/F41%/74[35–86]	5-FU	Pain (16%)/Diarrhea (10%)
Stein et al. (2016)/Europe	PL		mCRC/IV	1,249/F45%/ 74 [21–99]	Cape	Pain, Anemia, Diarrhea (12%)/ Nausea (8%)
Tominga et al.(2016)/Japan	R		CRC/III	135/F58%/63[58–71]	5FU/Cape	Neutropenia (52%)/ Anorexia (17%)
Tsuchihashi et al. (2018)/Japan	R		mCRC/IV	523/F41%/63[55–85]	Regorafenib, Trifluridine, Tipiracil	Hand-foot-syndrome (20%)/ Anemia (12%)
Watanabe et al. (2018)/Canada	PL		CRC/III	371/F49%/64[60–89]	Cape/5-FU	GI (80%)/ Neuropathy (80%)
Yamada et al. (2013)/Japan	P		mCRC/IV	512/F36%/63[33–79]	5-FU/OX	Neutropenia (43%)/ GI (12%)

Note. Cape: Capecitabine; CRC: colorectal cancer; F: female; GI: gastrointestinal; 5-FU: 5-Fluorouracil; mCRC: metastatic CRC; OX: oxaliplatin. Study designs P: prospective study design; PL: Prospective longitudinal design with repeated measures; R: retrospective design; RCT: randomized controlled trials. ^aToxicities measured by the Common Terminology Criteria for Adverse Events (CTCAE).

Table 1. B. Characteristics of Studies Not Included for Meta-Analysis (N = 5).

Table 1. B. Characteristics of Studies Not Included for Meta-Analysis (N = 5).

Authors(year) /Country	Study Design	Cancer Stages	Samples(N)/ F(%) /Mean Age [range]		Primary Regimens	Chemotoxicity Measures	Top prevalence of moderate-to-severe chemotoxicity subgroups
Brown et al. (2022)/USA	P	Colon/ II-III		533/F56%/ 59[47–70]	5-FU	Physicians’ chart and progress note review,	Discontinuation of chemotherapy (13%)
Cespedes Feliciano et al. (2017)/USA	P	Colon/ II-IV		533/F55.4%/ 59 [no data]	5-FU	Physicians’ chart and progress note review and EMR ICD9 Codes	Early discontinuation (36%)/Neuropathy (24.1%)
Decoster et al. (2018)/Europe	P	Older Adults mCRC/ IV		252/F38%/ 77[69–91]	5-FU	Physicians’ chart and progress note review	Vascular toxicity (35%)/ GI toxicity (13.6%)
Grimes, C. (2022)/USA	R	CRC/III		89/F58%/ 62[no data]	5-FU.	Physicians’ chart and progress note review	Diarrhea (6.7%)/ Nausea (5.6%)
Looijaard et al. (2020)/Europe	P	Older Adults Colon/III		53/F45%/ 71[68–74]	5-FU	Physicians’ chart and progress note review	Dose reduction/ incompletion (52.8%)

Note. CRC: colorectal cancer; EMR: electronic medical record; F: female; 5-FU: 5-Fluorouracil; GI: gastrointestinal; ICD-9: international classification of diseases, 9^th Revision (ICD-9); mCRC: metastasis CRC; PRO-CTCAE: patient-reported outcomes version of the common terminology criteria for adverse events.

3.3. Systematic Review: Prevalence and Risk Factors of Chemotoxicity

We reviewed the selected 30 studies based on the patient characteristics, interventional components, and primary outcomes (clinician-reported chemotoxicity) of the conceptual framework, Quality Health Outcomes Mode (Figure 1) [25].

3.3.1. Patient Characteristics

Among 12,706 samples across 30 studies, most participants were male (56%). Stage IV was the most prevalent, representing an average of 59% of participants, followed by stage III (28% of total samples). The mean age across the 30 studies was 68.4 years old. Age ranged from 58 [47] to 81 years old [44] across 30 studies. Ten studies [7,32,35,39,41,44,48,51,52,59] focused solely on older adults (> 65 years old) with the CRC population. The majority of participants were diagnosed with CRC, followed by colon cancer only (n = 6 [35,37,38,45,48,51]). Additionally, 14 studies were conducted on metastatic CRC (Table 1AB).

3.3.2. Interventional Components

Only Osterlund et al. (2007) [50] conducted an RCT with Lactobacillus intervention in metastatic CRC. Compared to the no-intervention groups, grade 3 or 4 diarrhea incidence was lower in patients treated with Lactobacillus (22% vs 37%, p =0.027). Additionally, these patients experienced less abdominal discomfort, required fewer hospital visits, and had a reduced number of chemotherapy dose reductions due to GI toxicity.

3.3.3. Primary Outcomes.

Clinician-reported chemotoxicity (Prevalence). The primary chemotherapy regimen in CRC was 5-FU-based agents, and the most common chemotoxicity measure was the Cancer Terminology Criteria for Adverse Events (CTCAE) grading scale, used in 25 studies among 30 selected studies. Five studies [37,38,39,43,48] assessed the prevalence of chemotoxicity by reviewing electronic health records (EHR), such as physicians’ charts and progress note reviews, which included the International Classification of Diseases (ICD)-9 codes (study n =1 [38]). The majority of the studies reported GI toxicity as the most prevalent type of moderate-to-severe chemotoxicity, from 12% to as high as 80% in different studies, except for 6 [37,38,45,48,49,56] out of 30 studies (Table 1AB). Diarrhea was a frequently reported symptom of GI toxicity in 11 studies [7,33,35,40,41,43,44,52,53,54,59] , with prevalence rates ranging from 8%[41] to 30% [35] across the studies. The next most frequently reported top-ranked moderate-to-severe chemotoxicity across the studies was neutropenia in 9 studies [32,36,40,42,45,50,55,57,59] with prevalence rates ranging from 8.1% [59] to 55% [42], followed by neuropathy in 5 studies [34,38,52,57], ranging from 13% [31] to 85.5%[34]. Three studies also evaluated chemotoxicity by examining the incidence of chemotherapy discontinuation or dose reduction/incompletion [37,38,48].

Clinician-reported chemotoxicity (Risk factors). Regarding risk factors of chemotoxicity (Table 2), four main categories were identified: nutritional status, geriatric assessment, biomarkers, and demographic/clinical factors. Fourteen studies [7,31,34,37,38,41,43,45,46,47,49,51,55,57] focused on malnutrition. The most common risk factor was low albumin levels [34,41,46,47,49,51,55]), followed by weight loss [7,34,41,46,47], low BMI [37,38,46], and low hemoglobin levels [47,57] before chemotherapy. Body composition, such as low muscle mass, sarcopenia, and high abdominal adiposity [37,38,43,45] were also significant factors. Body composition, including muscle and fat mass, were more sensitive risk factors of chemotoxicity than BMI, body weight, or body surface area. Seven studies [7,35,36,39,44,51,53] included a geriatric assessment, including comprehensive frailty score, physical frailty-grip status, or performance levels, showing that the baseline frailty status is associated with chemotoxicity. Various biomarkers were studied with two major categories: 1) Pro-inflammatory markers, e.g., white blood cell counts (WBC) [7,47,53], C-reactive protein (CRP) [47,51,55], lactate [40]; and 2) Hepato-renal functions [7,36,40,51]. Higher levels of low-density lipoprotein-derived lipids, short telomere length, lack of lactobacillus microbiome, and high carcinogenic antigen (CEA) were also shown to be associated with the risk of chemotoxicity. In demographic/clinical factors, the associations of age with chemotoxicity were inconsistent. Significant associations were found between younger adult age group (<50 years old) and neutropenia [42,47], as well as GI toxicity [42]. On the other hand, older age (> 65 years old) was significantly associated with GI toxicity [44,47] and hematological toxicity [47,57]. Female sex, cancer stages, previous history of aggressive chemotherapy or colorectal surgeries, and baseline HRQoL were also significantly associated with chemotoxicity (Table 2).

Table 2. Significant Predictorsa of Overall Chemotoxicity (moderate-to-severe).

Table 2. Significant Predictorsa of Overall Chemotoxicity (moderate-to-severe).

Authors(year)b/ Statistical methods	Nutrition	Geriatric assessments	Biomarkers	Demographic/ Clinical Factors
Ali et al.(2016)/ Group comparisons	Body mass with neuropathy
Backshall et al. (2011)/ Group comparisons			Metabolic lipid panel
Barret et al. (2011)/ Odds Ratios (ORs)	Weight loss, low albumin
Beukers et al. (2021)/ORs		Comprehensive Frailty		Female sex/ Cancer stages
Breton et al. (2021)/ORs		Physical Frailty (Performance)	Alkaline phosphatase (ALP)	Surgical history. Hx of aggressive chemotherapy
Feliu et al. (2022)/ Beta coefficient	Weight loss	Comprehensive Frailty	Kidney function
Folprecht et al. (2008)/ Group comparisons			High WBC, ALP, lactate
Gallois et al. (2019)/ ORs	Weight loss, low albumin
Garg et al. (2012)/ Beta Coefficient			Short telomere length, high platelet lymphocyte ratio, and low neutrophil count with hematological and GI toxicity.	Younger age with neutropenia and GI toxicity
Hochster et al. (2007)/ORs		Physical Frailty (Performance)	CEA, liver panels, creatine	Older age with GI toxicity (diarrhea)
Jung et al. (2015)/ORs	Psoas muscle mass
Karabulut et al. (2022)/ Group comparisons	Low BMI, Weight loss, low albumin
Li et al. (2021)/ORs	Weight loss with hand-foot syndrome, and nausea low Hemoglobin and albumin with hematological toxicity.		Increased WBC, high CRP with hematological toxicity	Older age with GI and hematological toxicity. Younger age with neutropenia.
Okada et al. (2017)/ Group comparisons	Low albumin with hepatotoxicity.
Osterlund et al. (2007)/ Group comparisons			Lactobacillus
Retornaz et al. (2020)/ORs	Low albumin	Physical Frailty (Grip strength, Performance)	Increased CRP, and ALP	Hx of aggressive chemotherapy
Seymour et al. (2011)/ORs		Physical Frailty (Performance)	Increased WBC	Baseline quality of life
Tominga et al. (2016/ORs	Low albumin.		CRP/Albumin ratio. elevated neutrophil to lymphocyte ratio
Watanabe et al. (2018)/ORs	Low Hemoglobin with hematological toxicity			Increased age & female sex with hematological toxicity
Studies not included in Meta-Analysis*
Brown et al. (2022)/ Group comparisons	BMI and abdominal adiposity
Cespedes Feliciano et al. (2017)/ORs	BMI, muscle mass index
Decoster et al. (2018)*/Group comparisons		Physical Frailty (Performance)
Grimes, C. (2022)/Group comparisons	Sarcopenia
Looijaard et al. (2020)/Group comparisons				Hx of aggressive chemotherapy

Note. Alb: albumin; BMI: body mass index; CEA: carcinoembryonic antigen; CRP: C-reactive protein; GI: gastrointestinal; Hx: history; ORs: odd ratios; USA: United States of America; WBC: white blood cell count. ^aAssociated with multiple chemotoxicity unless otherwise specified. ^bWe excluded studies with no significant risk factors (Antonio et al. 2018; Stein et al. 2016), or without examining risk factors of chemotoxicity (Aparicio et al. 2016; Sastre et al. 2012; Tsuchihashi et al. 2018; Yamada et al. 2013). *Studies not included in meta-analysis (n = 5) due to unavailable chemotoxicity prevalence data or data that was not comparable for inclusion in the meta-analyses.

3.4. Meta-Analysis: Prevalence and Risk Factors of Chemotoxicity

Among 30 studies analyzed in this review, 25 were included for meta-analysis when considering consistent chemotoxicity measures (i.e., CTCAE) (Table 1A).

3.4.1. Publication bias (asymmetry and heterogeneity) assessment

Among 25 studies in the meta-analysis, we performed the publication bias assessment, primarily based on the prevalence of overall moderate-to-severe chemotoxicity across 17 studies using the CTCAE grading scale (Asymmetry shown in Figure 3; Heterogeneity shown in Table 3). Then, we also performed a publication bias assessment based on the prevalence of chemotoxicity subgroups by the rank, from the selected 25 studies (Table 4 and Supplementary Figure 1). No asymmetries from Begg’s and Egger’s tests and funnel plots were found in the 25 selected studies included for meta-analysis (Table 3 and Table 4, Figure 3, and Supplementary Figure 1). Overall, high levels of heterogeneity were observed in chemotoxicity prevalence and its subgroups, with I² > 75%. Consequently, random-effect models were utilized to interpret results (Table 3 and Table 4).

3.4.2. Pooled prevalence of chemotoxicity

Moderate-to-severe chemotoxicity. The prevalence of moderate-to-severe overall chemotoxicity based on the CTCAE grading scale was reported in 17 studies [7,31,32,33,35,36,40,41,42,44,45,47,50,51,53,54,57]. The pooled prevalence of moderate-to-severe overall chemotoxicity was 45.7% (95% CI: 38.2 to 53.2) (Table 3 and Figure 4).

Table 3. Heterogeneity Tests for Publication Bias Among 17 Studies Included for Meta-Analysis of Prevalence of Overall Chemotoxicity (Moderate-to-Severe).

Table 3. Heterogeneity Tests for Publication Bias Among 17 Studies Included for Meta-Analysis of Prevalence of Overall Chemotoxicity (Moderate-to-Severe).

Study Characteristicsa	Sub-variables	Studies n/ Total Sample n	Pooled Prevalence of Overall Chemotoxicityd% (95% CI)	Test for heterogeneity between studiese
				Qdf Between	I2 (%) Between	p Between
Total Studiesa		17/n=8,819	45.7 (38.2 to 53.2)	112.5416	78.14	<.001
Countryb	Europe	12/n=7,793	45.4 (36.3 to 55.3)	154.6511	98.32	<.001
	Asia	2/n=462	40.1 (30.8 to 49.8)	223.531	99.41	.049
Publication year	2007-2010	3/n=2,896	46.1 (23.6 to 29.7)	158.392	95.49	.012
	2011-2015	4/n=894	37.0 (26.9 to 47.7)	133.413	98.65	.005
	2016-2020	6/n=2,294	55.9 (33.9 to 76.8)	148.855	95.42	.044
	2021-2024	4/n=2,735	47.5 (39.2 to 55.8)	133.523	88.41	.043
Study designc	Observational	16/n=8,669	45.5 (37.1 to 53.5)	140.8915	96.89	.023
Female prevalence	<50.0%	13/n=8,258	47.6 (37.6 to 57.7)	35.3212	91.23	.010
	≥ 50.0%	4/n=561	46.7 (42.6 to 50.8)	28.523	89.41	.043
Sample size	n < 100	4/n=301	40.5 (22.9 to 59.4)	158.423	78.75	.044
	100 ≤ n < 500	10/n=2,388	52.9 (39.6 to 65.9)	192.529	66.49	.013
	n ≥ 500	3/n=6,130	38.8 (24.3 to 54.5)	151.452	74.32	.007
Age group (Participants’ age range)	18 < age < 65	11/n=7,916	33.4 (22.3 to 39.5)	185.8910	85.65	.041
	65> Older Adults	6/n= 903	50.1 (27.6 to 69.9)	133.555	86.56	.035
Cancer Types	Colon only	4/n= 870	47.1 (42.3 to 51.8)	321.323	98.61	.019
	Mixed stages CRC	5/n=3,196	48.8 (32.0 to 65.7)	139.324	88.53	.043
	Metastatic CRC	7/n=4,520	41.9 (32.9 to 51.4)	98.496	89.65	.041

Note. CI: confidence intervals; CRC: colorectal cancer; df: degree of freedom; GI: gastrointestinal. ^a We included only 17 studies reporting overall chemotoxicity prevalence with moderate-to-severe severity using the Common Terminology Criteria for Adverse Events (CTCAE) measure among 25 studies included in the meta-analysis in our study. ^b We excluded Ali et al., Hochster et al., and Watanabe et al. as these studies are the sole representation of a particular country among a total of 25 selected studies of this study. ^c We excluded Osterlund et al. (2007) from the RCT study. ^d Moderate-to-severe toxicity; weighted effect size and standard error were applied, resulting in pooled prevalence and 95% Confidence Intervals (CIs). ^e p-value <.05 is considered significant for heterogeneity tests.

We also performed the subgroup analyses of the pooled prevalence of moderate-to-severe chemotoxicity by stratifying prevalence according to subgroups of chemotoxicity (e.g., non-hematological, hematological, and others) (Table 4, and funnel plots in Supplementary Figure 2). In moderate-to-severe chemotoxicity subgroups, the pooled prevalences of moderate-to-severe non-hematological and hematological toxicities were 39.2% (33.7 to 44.7) and 25.3% (19.4 to 31.5), respectively. Among moderate-to-severe other chemotoxicity subgroups, abdominal pain was the most frequent (24.3%), followed by GI toxicity (22.9%), neuropathy (17.9%), neutropenia (17.8%), nausea/vomiting (17.8%), and diarrhea (14.1%) (Table 4, and Supplementary Figure 2).

Mild chemotoxicity. Only a few studies reported the prevalence of chemotoxicity with mild severity. Six studies [7,32,50,51,53,55] were included for the pooled prevalence of mild overall chemotoxicity resulting in 61.7% of pooled prevalence. The pooled prevalences of mild non-hematological and hematological toxicities were 50.1% and 22.5%, respectively (Figure 5 and Table 4). Among chemotoxicity subgroups with mild severity (Table 4 and Supplementary Figure 3), diarrhea was the most frequent chemotoxicity (58.9%), followed by hand-foot syndrome (51.7%), anemia (36.5%), and mucositis/stomatitis (28.6%).

Table 4. Asymmetry and Heterogeneity Tests for Publication Bias: Subgroups of Chemotoxicity.

Table 4. Asymmetry and Heterogeneity Tests for Publication Bias: Subgroups of Chemotoxicity.

Study Sub-variables	Studies n/ Total sample n		Pooled Prevalence by rank (%: 95% CI)a	Asymmetry tests				Heterogeneity tests between studies
				Begg's test		Egger's test
				Kendall's Ƭ	pb	SE	pc	Qdf Between	I2 (%) Between		pb Between
Pooled Prevalence of Moderate-to-Severe Chemotoxicity
Non-Hematological Toxicity		16/n=6,602	39.2 (33.7 to 44.7)	0.34	.600	4.9	.943	121.6915	88.56	.033
Hematological Toxicity		19/n=6,882	25.3 (19.4 to 31.5)	0.29	.491	2.5	.423	132.6518	93.79			.049
Pooled Prevalence of Moderate-to-Severe Chemotoxicity Subgroups
Abdominal pain		3/n =1,655	24.3 (2.01 to 60.1)	0.33	.412	6.3	.143	56.12	99.61			<.001
GI Toxicity		20/n=9,489	22.9 (16.4 to 30.1)	0.23	.598	2.4.	.892	132.5219	98.59			<.001
Neuropathy		9/n=5,382	17.9 (4.9 to 36.5)	0.42	.394	3.2	.352	122.598	95.89			.049
Neutropenia		14/n=8,227	17.9 (11.1 to 25.9)	0.51	.341	5.3	.422	144.6513	98.51			<.001
Nausea/Vomiting		10/n=5,089	17.8 (8.5 to 29.6)	0.41	.535	5.6	.314	69.59	98.66			<.001
Diarrhea		18/n=7,209	14.1 (11.1 to 17.4)	0.31	.591	4.4	.289	144.0117	98.11			<.001
Leukocytosis		2/n=2,287	12.9 (0.4 to 38.2)	0.32	.542	3.4	.132	243.311	99.51			.035
Fatigue		7/n=2,772	12.6 (4.6 to 23.7)	0.38	.224	4.5	.499	132.566	99.92			<.001
Anemia		7/n=2,547	10.4 (4.5 to 18.3)	0.56	.621	3.4	.289	132.556	89.61			<.001
Leukopenia		3/n=4,452	10.2 (3.6 to 19.6)	0.41	.214	5.6	.512	241.952	89.52			.021
Mucositis/stomatitis		7/n=2,608	9.5 (2.9to 18.7)	0.59	.399	6.2	.526	87.46	95.41			.014
Hand-Foot-Syndrome		5/n=700	9.0 (1.8 to 20.9)	0.16	.841	6.5	.431	353.174	97.84			.019
Anorexia		5/n=1,804	6.4 (3.7 to 9.6)	0.41	.412	5.4	.122	101.424	99.41			<.001
Coagulation disorders		2/n=2,757	4.9 (4.1 to 5.8)	0.33	.312	5.5	.082	99.491	89.59			<.001
Constipation		2/n=341	3.4 (1.8 to 5.6)	0.14	.623	5.6	.412	93.041	84.23			.048
Pooled Prevalence of Mild Chemotoxicity
Overall Chemotoxicity		6/n=1,309	61.7 (48.0 to 74.6)	0.54	.841	2.3	.347	122.685	95.92			<.001
Non-Hematological Toxicity		3/n=473	50.1(21.1 to 78.9)	0.55	.792	3.1	.572	134.882	92.51			.002
Hematological Toxicity		4/n=913	22.1 (6.6 to 43.5)	0.41	.852	2.9	.123	156.413	85.91			.024
Pooled Prevalence of Mild Chemotoxity Subgroups
Diarrhea		4/n=956	58.9 (28.8 to 85.6)	0.41	.312	2.4	.312	111.313	78.41			.048
Hand-Foot-Syndrome		2/n=202	51.7 (0.4 to 98.8)	0.52	.411	4.1	.522	198.561	88.51			.009
Anemia		3/n=763	36.5 (1.5 to 84.9)	0.33	.012	2.3	.731	153.662	94.55			.014
Mucositis/stomatitis		3/n=884	28.6 (7.2 to 57.0)	0.28	.102	4.9	.341	142.652	93.41			<.001
Neutropenia		3/n=884	25.7 (6.2 to 52.3)	0.62	.531	5.3	.512	166.242	99.79			<.001
Nausea/Vomiting		3/n=1,572	18.3 (0.6 to 52.3)	0.38	.512	2.5	.823	143.662	95.12			<.001
Fatigue		2/n=492	17.1 (0.5 to 63.7)	0.12	.312	2.4	.623	98.421	98.55			.032
Coagulation disorders		2/n=1,422	4.3 (0.7 to 10.7)	0.52	.432	2.3	.412	102.031	85.66			.045

Note. CI: confidence intervals; GI: gastrointestinal; df = degree of freedom; SE: standard error. ^a Weighted effect size and standard error were applied, resulting in pooled estimates and 95% Confidence Intervals (CIs). ^b p <.05 considered significant publication bias. .

3.4.3. Pooled Associations of Age as a Predictor of Chemotoxicity Prevalence

In our review of significant risk factors for chemotoxicity (Table 2), we identified multiple inconsistencies. These inconsistencies were present in the types of statistical correlations used (e.g., ORs, Beta coefficients, or group comparisons) and in chemotoxicity subgroups (e.g., prevalences of overall toxicity, hematological, non-hematological, GI toxicities, or neutropenia). Given these inconsistencies, age was the only risk factor available for computing pooled associations with the prevalence of chemotoxicity (Table 5AB). In unadjusted meta-regression models (Table 5A), there were significant relationships between age (continuous variables) and chemotoxicity. When all other variables held constant, an increase of 1-year old in age was negatively associated with an average 1.09 change (unstandardized B= -1.09) in the prevalence of moderate-to-severe neutropenia (p = .003), while age was positively associated with an average change of B unites in the prevalence of nausea/vomiting (B = 1.32, p = .028), diarrhea (B = 1.05, p = .012), and GI toxicity (B = 1.02, p =.044). Given the standardized β coefficients in unadjusted models, age was the most significantly associated with GI toxicity (β = 1.97, p = .005), followed by the prevalence of neutropenia (β = -1.78, p =.002). In adjusted meta-regression models (controlling for cancer stages as the most prevalent cancer stage, metastatic status, cancer types, sample size as group variables, and sex as the most prevalent sex group variable), similar results were found, showing a negative association between age and neutropenia, while positive associations were found between age and nausea/vomiting, diarrhea, and GI toxicity prevalences. Given the standardized β coefficients in adjusted models (Table 5A), age was the most significantly associated with the prevalence of GI toxicity (β = 1.85, p = .001), followed by the prevalence of neutropenia (β = -1.44, p =.004). No significant relationship existed between age and overall, non-hematological, and hematological chemotoxicities in unadjusted and adjusted models (Table 5A).

Table 5B presents the results of a meta-ANOVA (F tests) and regressions (ORs) comparing the prevalence of different types of chemotoxicity between two age groups: adults (age > 18 and < 65 years old) and older adults (age > 65 years old). Significant differences existed in the prevalence of overall chemotoxicity, neutropenia, diarrhea, and GI toxicity between adults and older adults. The mean prevalences of overall chemotoxicity, diarrhea, and GI toxicity were higher in the older adult group compared to the adult group, while this was lower in the older adult group compared to the adult group for the prevalence of neutropenia. Compared to adult groups, older adult groups reported higher prevalences of chemotoxicity, with 14% in overall chemotoxicity (OR= 1.14), 27% in diarrhea (OR = 1.27), and 65% in GI toxicity (OR = 1.65). However, they reported a 35% lower prevalence of chemotoxicity in neutropenia (OR = 0.65).

4. Discussion

5. Conclusions

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