A prospective observational study of zinc deficiency symptoms during first-line chemotherapy for gastric and colorectal cancer

doi:10.21203/rs.3.rs-2731042/v1

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A prospective observational study of zinc deficiency symptoms during first-line chemotherapy for gastric and colorectal cancer

https://doi.org/10.21203/rs.3.rs-2731042/v1

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Background Zinc deficiency during long-term courses of chemotherapy and its related symptoms, including skin rash, taste disorder, and oral mucositis, has not been sufficiently investigated.

Methods This prospective observational study enrolled patients with gastric and colorectal cancer who underwent standard first-line chemotherapy. According to the Practice Guideline for Zinc Deficiency, zinc deficiency is defined as a serum level of < 60 μg/dL. Serum zinc levels were measured before and after (1, 3, and 6 months) chemotherapy, and symptoms were assessed using the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events version 1.0. Repeated measures were analyzed using a generalized linear mixed model.

Results Of the 61 enrolled patients, we analyzed 48 patients who underwent standard first-line chemotherapy with fluoropyrimidine plus oxaliplatin. Zinc deficiency was observed in 18 patients (38 %) before chemotherapy. The least-square means of serum zinc levels significantly decreased at 3 and 6 months of chemotherapy in 30 patients without zinc deficiency at the start of chemotherapy (both p < 0.01) but not in 18 patients with zinc deficiency at the start. Changes in serum zinc levels during chemotherapy were negatively correlated with taste changes, rash, and itching (all p < 0.04) in patients without zinc deficiency before treatment initiation.

Conclusions Serum zinc levels decreased during chemotherapy in zinc-non-deficient patients at the start of chemotherapy and were correlated with taste changes, skin rash, and itching. Therefore, it is necessary to investigate whether zinc supplementation can improve these symptoms.

Gastrointestinal cancer

Chemotherapy

Taste change

Rash

Itching

Zinc is an essential trace element required for more than 300 enzymatic activities [1]. Zinc deficiency has been reported to cause various symptoms, including dermatitis, hair loss, anemia, taste disorders, stunting, hypogonadism, diarrhea, osteoporosis, and delayed wound healing [1–5]. Zinc is absorbed in the distal duodenum and proximal jejunum and distributed throughout the human body [2]. A storage system for zinc does not exist in the body, and plasma zinc constitutes only 0.1% of the total body zinc [1]. Homeostatic mechanisms for zinc are fragile; therefore, a modest shortage of zinc intake causes its deficiency in the blood [6].

There are few reports on the relationship between serum zinc levels and its symptoms (taste disorder and oral mucositis) during cancer chemotherapy [7, 8]. However, the clinical state of zinc deficiency and its symptoms have not been sufficiently investigated during long-term courses of cancer chemotherapy.

The present study aimed to determine the prevalence of zinc deficiency before chemotherapy and the changes in zinc levels during chemotherapy. In addition, we elucidated symptoms that may be related to zinc deficiency during first-line chemotherapy for unresectable gastric and colorectal cancers.

Study design and patients

This was an exploratory and prospective observational study of zinc deficiency in patients with gastric and colorectal cancers who underwent standard first-line chemotherapy at the National Hospital Organization Shikoku Cancer Center from August 2020 to September 2021. The cutoff date for data collection was December 31, 2022.

The eligibility criteria were age ≥ 20 years; unresectable advanced or recurrent gastric or colorectal cancer; previously untreated disease except for neoadjuvant and adjuvant chemotherapy; Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, 1, or 2; and adequate organ function for standard chemotherapy. Patients were excluded if they took zinc acetate hydrate supplements at registration, could not tolerate oral intake or enteral nutrition, or were judged to be unable to answer the questionnaire.

This study was approved by the institutional ethics review board of our hospital and complied with the Japanese ethical guidelines [9]. Written informed consent was obtained from all the patients before enrollment in the study.

Data Collection And Assessments

The following clinical parameters were assessed: sex, age, ECOG PS, primary tumor site, organ metastasis, peritoneal dissemination, ascites, gastrojejunostomy or duodenal resection, body mass index, and serum levels of albumin. Duodenal resection included distal/total gastrectomy and pancreaticoduodenectomy.

Tumor response, progression-free survival (PFS), and overall survival (OS) were assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 to investigate whether zinc deficiency affected the efficacy of chemotherapy and prognosis. PFS was defined as the time from the start of chemotherapy to disease progression or death due to any cause. OS was defined as the time from the start of chemotherapy to death due to any cause.

Serum zinc levels were measured before and after (1, 3, and 6 months) chemotherapy, and eight symptoms were assessed using the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE®), version 1.0 [10]. PRO-CTCAE is a measurement system for 78 symptom items drawn from the Common Terminology Criteria for Adverse Events (CTCAE) by self-reports from patients in cancer clinical trials [11]. The response score of the PRO-CTCAE is 0–4 (frequency, severity, interference, and amount) or 0–1 (presence/absence). We selected eight symptoms of interest (mouth/throat sores, taste changes, rash, skin dryness, acne, hair loss, itching, and nail ridging) that are presumed from the literature to be associated with zinc deficiency [1–8].

Blood samples for measurement of serum zinc levels were obtained a few hours after breakfast. Serum zinc levels were measured using Nitro-PAPS (FALCO Biosystems Ltd., Kyoto, Japan) [12]. According to the Practice Guideline for Zinc Deficiency, zinc deficiency was defined as a serum level of < 60 µg/dL, and borderline zinc deficiency was defined as a serum level of ≥ 60 µg/dL to < 80 µg/dL [13].

The physician in charge of each patient administered zinc acetate hydrate when necessary. Data after administration of zinc acetate hydrate or discontinuation of chemotherapy were excluded from the analyses.

Statistical Analyses

Data were analyzed using the JMP Pro Version 16.0. (SAS Institute Inc., Cary, NC, USA), EZR version 1.5 and R version 4.0.2 [14]. Statistical significance was set at p < 0.05. The chi-square test and Wilcoxon rank-sum test were used to evaluate proportional differences between the two groups. Repeated measures were analyzed using linear mixed models and generalized linear mixed models. Five factors believed to affect PRO-CTCAE and zinc deficiency were set as fixed effects in the generalized linear mixed model: age, chemotherapy regimen (SOX, tegafur/gimeracil/oteracil, and oxaliplatin; FOLFOX, 5-fluorouracil/leucovorin, and oxaliplatin; XELOX, capecitabine, and oxaliplatin), anti-epidermal growth factor receptor (EGFR) antibody, gastrojejunostomy or duodenal resection, and primary tumor (gastric and colorectal cancer).

Patients

Sixty-one patients were enrolled in the study. Fifty-nine patients were treated with various regimens (Fig. 1) after excluding two ineligible patients (ECOG PS 3 and administration of zinc acetate hydrate). We analyzed 48 patients who underwent standard first-line chemotherapy with fluoropyrimidine plus oxaliplatin (FPOX) to reduce the bias of the different regimens used. The median age of the patients was 71 years (Table 1). Most patients had an ECOG PS performance status of 0 or 1. Thirty patients had gastric cancer, and 18 had colorectal cancer. Several patients were treated with anti-human epidermal growth factor receptor 2, anti-vascular endothelial growth factor, and anti-epidermal growth factor receptor (EGFR) antibodies, in addition to FPOX.

Table 1

Characteristics of patients treated with first-line chemotherapy with fluoropyrimidine plus oxaliplatin
		All patients (n = 48)	Zinc deficiency status		P value*
		All patients (n = 48)	Non-deficiency (ND) group (n = 30)	Deficiency (D) group (n = 18)	P value*
Sex
	Male (%)	26 (54)	14 (47)	12 (67)	0.18
	Female (%)	22 (46)	16 (53)	6 (33)
Age
	Median (range)	71 (34–89)	69 (34–85)	74 (64–89)	0.04
Performance status
	0 (%)	22 (46)	16 (53)	6 (33)	0.26
	1 (%)	22 (46)	11 (37)	11 (61)
	2 (%)	4 (8)	3 (10)	1 (6)
Primary site
	Stomach (%)	30 (63)	17 (57)	13 (72)	0.28
	Colorectum (%)	18 (38)	13 (43)	5 (28)
No. of metastatic sites
	0, 1 (%)	20 (42)	13 (43)	7 (39)	0.19
	2 (%)	12 (25)	5 (17)	7 (39)
	≥ 3 (%)	16 (33)	12 (40)	4 (22)
Peritoneal dissemination
	Yes (%)	23 (48)	15 (50)	8 (44)	0.71
	No (%)	25 (52)	15 (50)	10 (56)
Ascites
	Yes (%)	7 (15)	5 (17)	2 (11)	0.60
	No (%)	41 (85)	25 (83)	16 (89)
Gastrojejunostomy or resection of duodenum^†
	Yes (%)	9 (19)	6 (20)	3 (17)	0.77
	No (%)	39 (81)	24 (80)	15 (83)
Body mass index
	Median (range)	22.3 (15.3–31.2)	22.3 (15.3–31.2)	22.3 (15.7–27.9)	0.47
Serum level of albumin (g/dL)
	Median (range)	3.5 (1.9–4.6)	3.6 (2.4–4.6)	3.3 (1.9–4.2)	0.08
Serum level of zinc (µg/dL)
	Median (range)	64.0 (31–85)	69.5(60–85)	55.0 (31–59)	< 0.0001
Regimen (%)
	FPOX	34 (71)	20 (67)	14 (78)	0.77
	FPOX + trastuzumab	2 (4)	1 (3)	1 (6)
	FPOX + bevacizumab	8 (17)	6 (20)	2 (11)
	FPOX + panitumumab	4 (8)	3 (10)	1 (6)
^* Chi-square test and Wilcoxon rank-sum test.
^† resection included distal gastrectomy, total gastrectomy, and pancreaticoduodenectomy.
FPOX: fluoropyrimidine plus oxaliplatin.

Zinc Deficiency

Before first-line chemotherapy, 38% of the patients had zinc deficiency. The incidence of abnormal PRO-CTCAE symptoms in patients with or without zinc deficiency before chemotherapy is shown in Fig. 2. Although mouth/throat sores, and taste and rash changes tended to be frequent in patients with zinc deficiency before chemotherapy, the incidence of these symptoms was not significantly different between patients with and without zinc deficiency. The severity of all symptoms graded using PRO-CTCAE was almost mild.

Analyses In Zinc-non-deficient (Nd) And Zinc-deficient (D) Patients

Considering that a substantial number of patients showed zinc deficiency before chemotherapy, we analyzed the data by dividing the patients into two groups: zinc-non-deficient patients (ND group, n = 30) and zinc-deficient patients (D group, n = 18). Table 1 shows the patient characteristics of the two groups before chemotherapy. The median age was significantly lower in the ND group than in the D group (p = 0.04); however, other parameters, including the anti-EGFR antibody combination, did not differ between the two groups.

The response (complete plus partial response) rates were 24% (4/17) and 38% (5/13) in the ND and D groups, respectively, in patients with gastric cancer (p = 0.38). The response rates were 38% (5/13) and 40% (2/5) in the ND and D groups, respectively, in patients with colorectal cancer (p = 0.95). The PFS and OS did not differ between the ND and D groups in patients with gastric or colorectal cancer (Fig. 3).

The proportion of zinc deficiency in the ND group increased as the treatment progressed (Fig. 4a), whereas that in the D group improved to approximately half of the patients one month after chemotherapy (Fig. 4b). Figure 4c shows the changes in the serum zinc levels in the ND and D groups using a linear mixed model. The least-square mean (LSM) of serum zinc levels at 3 and 6 months of chemotherapy was significantly lower than that before chemotherapy in the ND group (p = 0.007 and p < 0.001, respectively). In contrast, LSM at one month of chemotherapy was significantly higher than that before chemotherapy in the D group (p = 0.037). The zinc levels of eight patients in the D group increased to over 60 µg/dL after one month of chemotherapy. The initial responses of these patients were partial response (n = 2) and stable disease (n = 6).

Correlations Of Pro-ctcae Symptoms And Serum Zinc Levels In The Nd And D Groups

The incidences of the eight PRO-CTCAE symptoms that emerged during first-line chemotherapy are shown in Table 2. Although the incidence of ≥ grade 2 and ≥ grade 3 taste changes, skin dryness, hair loss, and itching tended to be higher in the ND group than in the D group, there were no statistically significant differences between the two groups at the various cutoff grades.

Table 2

Incidence of symptoms presumed to be associated with zinc deficiency according to the grades of patient-reported common terminology criteria for adverse events (PRO-CTCAE) during first-line chemotherapy with fluoropyrimidine and oxaliplatin
Symptoms (Attribute, grade range)	Zinc-non-deficient (ND) group, n = 30			Zinc-deficient (D) group, n = 18
	Grade			Grade
	1 or more	2 or more	3 or more	1 or more	2 or more	3 or more
Mouth/throat sores (Severity, 0–4) (%)	11 (37)	2 (7)	0 (0)	5 (28)	1 (6)	0 (0)
Taste changes (Severity, 0–4) (%)	15 (50)	6 (20)	3 (10)	10 (54)	2 (11)	0 (0)
Rash (Presence/Absence, 0–1) (%)	9 (30)	- -	- -	5 (28)	- -	- -
Skin dryness (Severity, 0–4) (%)	18 (60)	6 (20)	1 (3)	7 (39)	0 (0)	0 (0)
Acne (Severity, 0–4) (%)	9 (30)	2 (7)	1 (3)	2 (11)	1 (6)	1 (6)
Hair loss (Amount, 0–4) (%)	9 (30)	6 (20)	3 (10)	2 (11)	1 (6)	0 (0)
Itching (Severity, 0–4) (%)	15 (50)	5 (17)	2 (7)	4 (22)	0 (0)	0 (0)
Nail ridging (Presence/Absence 0, 1) (%)	7 (23)	- -	- -	5 (28)	- -	- -

Next, the correlations between symptoms (present or absent during chemotherapy) and serum zinc levels were analyzed using a generalized linear mixed model (Table 3). Taste changes, skin rashes, and itching were significantly negatively correlated with serum zinc levels in the ND group (P = 0.038, 0.031, and 0.037, respectively). No symptoms correlated with serum zinc levels in the D group.

Table 3

Relationship between emerging symptoms and serum zinc levels analyzed using the generalized linear mixed model*
	Odds ratio	Estimate	Standard error	P value^*
Zinc non-deficiency(ND group)(n = 30)
Mouth/throat sores	0.988	-0.013	0.025	0.611
Taste changes	0.943	-0.059	0.029	0.038
Rash	0.887	-0.120	0.056	0.031
Skin dryness	0.952	-0.049	0.025	0.053
Acne	0.952	-0.049	0.033	0.140
Hair loss	0.973	-0.028	0.033	0.407
Itching	0.951	-0.051	0.024	0.037
Nail ridging	0.960	-0.041	0.035	0.247
zinc deficiency(D group)(n = 18)
Mouth/throat sores	1.049	0.048	0.032	0.134
Taste changes	1.070	0.067	0.035	0.052
Rash	1.017	0.017	0.034	0.613
Skin dryness	0.974	-0.027	0.035	0.442
Acne	-	-	-	-
Hair loss	-	-	-	-
Itching	1.067	0.065	0.035	0.067
Nail ridging	1.043	0.043	0.034	0.205
*All analyses were performed by categorizing symptoms as absent (grade 0) or present (grade 1 or more). The models were adjusted for age, chemotherapy regimen (tegafur/gimeracil/oteracil and oxaliplatin, 5-fluorouracil/leucovorin and oxaliplatin, and capecitabine and oxaliplatin), anti-epidermal growth factor receptor antibody, gastrojejunostomy or resection of the duodenum, and primary tumor (gastric and colorectal cancer).

In this study, serum zinc levels in the ND group significantly decreased during chemotherapy, whereas those in the D group demonstrated no further decrease. It is noteworthy that serum zinc behavior was different between ND and D patients. Furthermore, serum zinc levels were negatively correlated with the incidence of PRO-CTCAE symptoms including taste changes, skin rash, and itching in the ND group.

The proportion of zinc deficiency before first-line chemotherapy with FPOX in gastric and colorectal cancer patients is high at approximately 40%, relative to that reported in the Japanese literature of voluntary health checkups at 0.4% − 0.6% [15]. This indicates that these cancer patients were highly likely to be in a zinc-deficient state before chemotherapy. This may be due to decreased zinc intake and absorption, inflammation, and downregulation of ZRT and IRT-like protein (ZIP; a zinc transporter) in cancers [16–18]. It has also been reported that low zinc intake is related to the risk of gastrointestinal cancer, and cancer biology seems to be strongly associated with zinc intake [19].

There was a significant difference between the ND and D groups only in terms of age. This reflects the natural course of aging, as reported epidemiologically [15, 20]. There were no significant differences between the two groups in terms of the other baseline characteristics. Serum albumin level was slightly lower in the D group, suggesting impaired nutrition.

As treatment progressed, the number of patients with zinc deficiency increased in the ND group. The serum zinc levels in the ND group decreased, whereas those in the D group did not. One reason for the zinc decrease in the ND group is the direct effect of the zinc chelating ability of fluorouracil [21]. Another reason may be decreased food intake and absorption due to chemotherapy-induced gastrointestinal mucosal injury. However, the maintained zinc levels in the D group were inconsistent with these reasons, suggesting some mechanisms for maintaining blood zinc levels in a zinc-deficient state. Further studies are warranted to confirm these findings.

Interestingly, serum zinc levels significantly increased in the D group at one month of chemotherapy, and the proportion of normal zinc levels over 80 µg/dL appeared to increase in the ND and D groups (Fig. 4). These findings suggest an improvement in oral intake and nutritional status due to effective chemotherapy in some patients. The first tumor responses of patients in the D group, whose serum zinc levels changed from deficient to non-deficient status at one month of chemotherapy, were all partial responses and stable disease, and no patient progressed.

We considered various cutoff points for PRO-CTCAE grades but did not find any significant differences in the incidences and grades of symptoms between the ND and D groups. However, generalized mixed model analyses showed that serum zinc levels were negatively correlated with the incidences of taste changes, rash, and itching among the symptoms of interest in the ND group over time. Recently, an interventional study showed that zinc acetate hydrate did not improve chemotherapy-induced dysgeusia in patients with gastrointestinal cancer, which suggested no correlation between zinc deficiency and dysgeusia [7]. This is inconsistent with our findings. However, it is difficult to compare our results to theirs because patient selection differed between the studies, and the correlation between taste changes and serum zinc levels was observed only in the ND group in our study. The skin is known to be one of the systems that is most susceptible to zinc deficiency, hence the rash and itching [1]. We also reported that a zinc homeostasis disorder might cause the development of skin xerosis in patients with colorectal cancer treated with FPOX plus anti-EGFR antibody [22]. The skin conditions and zinc levels appeared to be closely correlated.

The present study had some limitations. Although this study was exploratory, its sample size was small. However, we specified possible symptoms related to zinc deficiency; further investigations with larger sample sizes are warranted. Furthermore, it is necessary to ensure that patients’ backgrounds are as uniform as possible. Symptoms were assessed using the PRO-CTCAE in this study. The feasibility of this tool has not been adequately assessed in this setting. Therefore, it is necessary to concurrently use other measurement tools in the future.

In conclusion, serum zinc levels decreased during the course of chemotherapy in patients who were zinc- non-deficient before chemotherapy, and this decrease was related to the frequency of taste changes, rash, and itching. We plan to conduct an interventional study using zinc to improve these symptoms.

Acknowledgements

We would like to thank Editage (www.editage.com) for English language editing.

Author contributions

CS, TN, MT, and IH contributed to the conception and design of the study. Material preparation and data collection were performed by CS, TN, KH, AA, YO, TK, and SN. The analysis was performed by CS and NY. CS wrote the first draft of the manuscript. The review and editing were performed by TN, YK, IH, and HO. All authors commented on the previous versions of the manuscript. All authors have read and approved the final manuscript.

Funding

This study did not receive any specific grant from public, commercial, or not-for-profit funding agencies.

Conflict of interest

TN reports honoraria from Ono Pharmaceutical Co., Ltd., Bristol Myers Squibb, and Taiho Pharmaceutical Co., Ltd., and reports research funding from Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., MSD K.K., Daiichi Sankyo Co., Ltd., Bristol Myers Squibb, and Astra Zeneca. TK reports honoraria from Eli Lilly Japan K.K., Chugai Pharmaceutical Co., Ltd., Bristol Myers Squibb, Taiho Pharmaceutical Co., Ltd., and Ono Pharmaceutical Co., Ltd. IH received advisory fees from Asahi Kasei Co., Ltd., Merck Biopharma Co., Ltd., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., and Taiho Pharmaceutical Co., Ltd., and reports honoraria from Taiho Pharmaceutical Co., Ltd., Yakult Honsha Co., Ltd., and Ono Pharmaceutical Co., Ltd.

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A prospective observational study of zinc deficiency symptoms during first-line chemotherapy for gastric and colorectal cancer

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Version 1

Abstract

Figures

Introduction

Patients And Methods

Study design and patients

Data Collection And Assessments

Statistical Analyses

Results

Patients

Zinc Deficiency

Analyses In Zinc-non-deficient (Nd) And Zinc-deficient (D) Patients

Correlations Of Pro-ctcae Symptoms And Serum Zinc Levels In The Nd And D Groups

Discussion

Declarations

References

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