2024 Volume 47 Issue 3 Pages 732-738
Hypomagnesemia is a characteristic adverse event of cetuximab in patients with head and neck cancer (HNC). However, there is limited information about its prevalence, risk factors, and preventive strategies. This study aimed to investigate the risk factors of hypomagnesemia and examine the preventive effects of prophylactic magnesium (Mg) administration. We initially investigated HNC patients treated with cetuximab between 2013 and 2019. Our institute started prophylactic Mg treatment (20-mEq Mg sulfate administration before cetuximab) in practice during this period. We retrospectively assess the preventive efficacy by comparing patients before and after its implementation. In total, 109 patients were included. In 60 patients without prophylaxis, all-grade and grade ≥2 hypomagnesemia at 3 months occurred in 61.7 and 15.0% of patients. The incidence of hypomagnesemia was not affected by regimens and concomitant medications. In 49 patients treated with prophylactic Mg treatment, there was no significant decrease in the cumulative incidence of hypomagnesemia. However, the preventive Mg treatment eliminated the need for additional Mg repletion to maintain Mg levels in patients treated with paclitaxel + cetuximab. A risk factor in patients without prophylaxis was a low Mg level at pre-treatment (≤2.0 mg/dL) (odds ratio: 6.03, 95% confidence interval: 1.78–20.4, p = 0.004), whereas that in patients with prophylaxis was the number of cetuximab doses (≥10) (odds ratio: 5.50, 95% confidence interval: 1.52–19.87, p = 0.009). In conclusion, a low pre-treatment Mg level was the only risk factor that could be avoided by prophylactic Mg administration. This preventive intervention is recommended for managing cetuximab-induced hypomagnesemia.
Cetuximab (Cmab), a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), received approval in 2006 for advanced head and neck cancer (HNC).1) Its use in combination therapies, including 5-fluorouracil plus cisplatin (FP) or paclitaxel (PTX) with Cmab, has demonstrated efficacy in managing unresectable and recurrent HNC.2–4) A distinctive adverse event associated with Cmab therapy is hypomagnesemia, characterized by a gradual decline in the serum magnesium (Mg) level undergoing Cmab administration.5,6) The onset of hypomagnesemia not only causes discontinuation of Cmab treatment but can also give rise to symptoms like fatigue, tremors, nausea and vomiting, and, in severe cases, cardiac rhythm abnormalities.
Several studies have investigated the incidence and risk factors of Cmab-induced hypomagnesemia in real-world HNC patients. Enokida et al. reported an overall incidence of hypomagnesemia at 50.4%, with concurrent administration of platinum anti-cancer drugs described as an independent risk factor.7) However, the occurrence of hypomagnesemia in the PTX + Cmab regimen, which plays a pivotal role in the post-immune checkpoint inhibitor era, remains unclear. Additionally, there is a need to elucidate the extent to which renal toxicity induced by platinum drugs or administration of loop diuretics for cisplatin (CDDP)-related hydration therapy exacerbates hypomagnesemia during Cmab treatment. Quantifying the impact of each risk factor facilitates the development of effective management for Cmab-induced hypomagnesemia.
In the presence of hypomagnesemia, repeated intravenous injections of Mg sulfate are administered to stabilize serum Mg levels. However, a systematic review focusing on EGFR inhibitor-induced hypomagnesemia revealed that high-dose intravenous Mg replacement had difficulty achieving sustained normal Mg levels in patients with severe hypomagnesemia.8) Therefore, the prophylactic management of serum Mg levels from initiating Cmab treatment is deemed important. Various clinical approaches to managing hypomagnesemia, such as the oral administration of Mg oxide tablets, have been explored. However, these methods have proven inconsistent and intolerable due to associated diarrhea, which can lead to further Mg loss.8–10) Considering these factors, our institute has implemented prophylactic intravenous Mg sulfate administration as a clinical practice for several years.
In this study, our primary objective is to scrutinize strategies to prevent Cmab-induced hypomagnesemia and alleviate patient burden. Initially, we investigated differences in Cmab-induced hypomagnesemia between regimens in patients with advanced HNC and explored how concomitant medications, including loop diuretics, contribute to the development of hypomagnesemia. Secondly, given our institute’s initiation of prophylactic intravenous magnesium sulfate administration a couple of years ago, our goal is to retrospectively assess the preventive efficacy of this method against hypomagnesemia by comparing patients before and after its implementation.
This retrospective observational study was approved by the Institutional Review Board of Kyushu University Graduate School and Faculty of Medicine (Approval Number: 2020-260) and conducted in accordance with the Declaration of Helsinki. The requirement for informed consent was waived owing to the retrospective nature of the study, and the patients were allowed to discontinue the study through an opt-out method on our official website.
Study Design and PatientsWe retrospectively reviewed the medical records of patients with HNC treated with Cmab between January 2013 and December 2019 at Kyushu University Hospital. Patients who received Cmab during clinical trials, lacked a baseline Mg value, were lost to follow-up, and discontinued Cmab due to an infusion reaction were excluded. The end of the follow-up period was September 2022. The development of hypomagnesemia was investigated, including information about the patient’s background, prior treatments, regimens, clinical outcomes, and concomitant medications (e.g., loop diuretics, thiazide diuretics, proton pump inhibitors (PPIs), amphotericin B, cyclosporine, and aminoglycoside antibiotics). The severity of hypomagnesemia was determined using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0, as follows: grade 1, Mg level of 1.8–1.2 mg/dL; grade 2, Mg level of 1.1–0.9 mg/dL; grade 3, Mg level of 0.8–0.7 mg/dL; and grade 4, Mg level of <0.7 mg/dL. For patients with serum Mg levels below the baseline (1.8 mg/dL) before treatment, the onset of Cmab-induced hypomagnesemia was defined if the grade was exacerbated after treatment started.
At Kyushu University Hospital, prophylactic intravenous Mg sulfate administration was started in the FP/FC + Cmab group in June 2015 and in the PTX + Cmab group in July 2018 as clinical practice. Mg sulfate (1 mEq/mL, 20 mL) was administered on day 1 in the FP + Cmab group and on days 1, 8, 15, and 22 in the PTX + Cmab group. Firstly, the prevalence of hypomagnesemia and the influence of concomitant medications were examined using only data from patients without prophylactic Mg administration (n = 60). Secondly, the efficacy of prophylactic Mg administration to prevent hypomagnesemia was examined in patients with (n = 60) or without (n = 49) prophylaxis.
Statistical AnalysisThe results are expressed as odds ratios (OR) with 95% confidence intervals (CI). Competing risk analysis was used to calculate the cumulative incidence of hypomagnesemia, and statistical analyses were performed using the Gray test with Bonferroni correction, with the end of Cmab treatment without hypomagnesemia defined as a competing risk. Data of the two groups were compared using the Mann–Whitney U test, Wilcoxon matched-pairs test, paired t-test, and unpaired t-test. The correlation between the two variables was analyzed using Pearson correlation coefficient analysis. Clinical variables in patients dichotomized by prophylactic Mg treatment were compared using the Fisher exact test. Multivariate analysis of the incidence of hypomagnesemia and patient characteristics was performed using logistic regression analysis, and the covariates were selected from risk factors in previous studies: baseline Mg level, number of Cmab administration, and concurrent platinum usage.7) All statistical analyses were performed using GraphPad Prism, version 9.4.0 (GraphPad Software, La Jolla, CA, U.S.A.), EZR, version 1.55 (Saitama Medical Center, Jichi Medical University, Saitama, Japan),11) which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria), and JMP, version 16.0.0 (SAS Institute, Inc., Cary, NC, U.S.A.). All tests were two-sided, and statistical significance was set at p < 0.05.
In total, 141 patients with HNC treated with Cmab were retrospectively evaluated. Except for patients who met the exclusion criteria (n = 32), 109 patients were selected for further analysis (Fig. 1). The median age was 66 years (33–86 years), and 78.0% of the patients were male. Primary tumor sites were the nasopharynx (4.6%), oropharynx (22.9%), hypopharynx (14.7%), larynx (11.0%), oral cavity (18.3%), sinonasal tract (16.5%), external auditory canal (5.5%), and others/unknown (6.4%). Patients who did not receive prophylactic Mg treatment received FP + Cmab (n = 18), FC + Cmab (n = 11), PTX + Cmab (n = 13), and Cmab + radiotherapy (n = 18). Patients who received prophylactic Mg treatment received FP + Cmab (n = 39) and PTX + Cmab (n = 10).
Mg, magnesium; FP, 5-fluorouracil + cisplatin; FC, 5-fluorouracil + carboplatin; Cmab, cetuximab; PTX, paclitaxel.
Among 60 patients without prophylactic Mg treatment, cumulative incidences of all-grade and grade ≥2 hypomagnesemia at 3 months were 61.7 and 15.0%, respectively, and there were no significant differences between regimens (Figs. 2a, b). The average decrease in serum Mg levels from baseline to the worst value was 24.9% (from 1.98 to 1.48 mg/dL; Fig. 2c). This reduction was consistent among the patients treated with different regimens: FP + Cmab (26.4%), FC + Cmab (26.6%), PTX + Cmab (24.1%), and Cmab + radiotherapy (23.0%) (Figs. 2d–g). The median number of Cmab administrations was similar in patients treated with FP + Cmab (14.5 doses), FC + Cmab (11 doses), and PTX + Cmab (12 doses). Patients treated with Cmab + radiotherapy showed significantly fewer Cmab administrations (7 doses) than those treated with the other regimens (Supplementary Fig. 1a). The number of Cmab doses did not correlate with the incidence of hypomagnesemia in receiver operating characteristic (ROC) curve analysis (Supplementary Figs. 1b, c).
(a) Cumulative incidences of all-grade and (b) grade ≥2 hypomagnesemia in patients treated with FP + Cmab (n = 18), FC + Cmab (n = 11), PTX + Cmab (n = 13), and Cmab + radiotherapy (n = 18). (c) The difference in serum Mg between pre-treatment and worst values after treatment initiation in all patients and (d) in patients treated with FP + Cmab, (e) FC + Cmab, (f) PTX + Cmab, and (g) Cmab + radiotherapy. Data are shown as the mean with the standard error of the mean. Significance was determined using the paired t-test. *** p < 0.005, and **** p < 0.001. Mg, magnesium; FP, 5-fluorouracil + cisplatin; FC, 5-fluorouracil + carboplatin; Cmab, cetuximab; PTX, paclitaxel.
We systematically investigated concomitant medications associated with hypomagnesemia, including PPIs, loop diuretics, thiazide diuretics, amphotericin B, cyclosporine, and aminoglycoside antibiotics. Among the cohort of 60 patients, 22 (36.7%) and 2 (3.3%) were administrated loop and thiazide diuretics, respectively, while 34 (56.7%) received PPIs, and one patient (1.7%) received cyclosporine during Cmab treatment. Evaluating patients with or without loop diuretics revealed that cumulative incidences of all-grade hypomagnesemia at 3 months were 72.7 and 55.3%, respectively (Fig. 3a). Similarly, in patients treated with or without PPIs, cumulative incidences of all-grade hypomagnesemia at 3 months were 55.9 and 69.2%, respectively (Fig. 3b). No statistically significant differences were observed in the cumulative curves with or without concomitant medications. Furthermore, although platinum drugs are recognized contributors to hypomagnesemia, cumulative doses of CDDP and CBDCA did not exhibit a significant correlation with serum magnesium reduction (Supplementary Figs. 2a, b).
(a) Cumulative incidence of all-grade hypomagnesemia in patients treated with (n = 22) and without (n = 38) loop diuretics. (b) Cumulative incidence of all-grade hypomagnesemia in patients treated with (n = 34) and without (n = 26) PPIs. Significance was determined using the Gray test. PPIs, proton pump inhibitors.
In patients treated with (n = 60) and without (n = 42) prophylactic Mg treatment, there were no significant differences in age, sex, the primary tumor site, number of Cmab doses, or baseline serum Mg level (Table 1). Patients treated with FC + Cmab were included in only the non-prophylactic group. The incidence of all-grade hypomagnesemia at 3 months was 61.7% among patients without prophylactic Mg, whereas that was decreased to 49.0% among those with prophylactic Mg (Fig. 4a). The incidence of grade ≥2 hypomagnesemia decreased from 11.7 to 2.0% at 2 months and from 15.0 to 8.2% at 3 months due to prophylactic Mg treatment (Fig. 4b). Although these reductions were confirmed regardless of the administered regimen (Figs. 4c, d), there were no significant differences in the cumulative curve of hypomagnesemia. In patients treated with the FP/FC + Cmab regimen, the number of patients who required additional Mg sulfate to maintain serum Mg levels was similar in both groups (Fig. 4e). However, patients who received PTX + Cmab with prophylaxis did not require additional Mg administration (Fig. 4f). Adverse events related to prophylactic administration included hypermagnesemia (n = 1, 2.0%; maximum Mg level: 2.6 mg/dL) and vascular pain during Mg administration (n = 1, 2.0%). Hypermagnesemia also occurred in the non-prophylactic group (n = 3, 5.0%, maximum Mg level: 2.8 mg/dL), but there was no significant increase in hypermagnesemia with prophylactic Mg administration.
| Characteristics | Prophylactic Mg treatment (−), n = 60 | Prophylactic Mg treatment (+), n = 49 | p-Value |
|---|---|---|---|
| Age—median (range) | 65.5 (39–86) | 66.0 (33–79) | 0.993 |
| Sex, male—n (%) | 48 (80.0%) | 37 (75.5%) | 0.645 |
| Primary tumor site—n (%) | 0.658 | ||
| Nasopharynx | 4 (6.7%) | 1 (2.0%) | |
| Oropharynx | 15 (25.0%) | 10 (20.4%) | |
| Hypopharynx | 10 (16.7%) | 6 (12.2%) | |
| Larynx | 8 (13.3%) | 4 (8.2%) | |
| Oral cavity | 8 (13.3%) | 12 (24.5%) | |
| Sinonasal tract | 8 (13.3%) | 10 (20.4%) | |
| External auditory canal | 4 (6.7%) | 2 (4.1%) | |
| Others/unknown | 3 (5.0%) | 4 (8.2%) | |
| Treatment regimens—n (%) | < 0.001 | ||
| FP + Cmab | 18 (30.0%) | 39 (79.6%) | |
| FC + Cmab | 11 (18.3%) | 0 (0.0%) | |
| PTX + Cmab | 13 (21.7%) | 10 (20.4%) | |
| Cmab + RT | 18 (30.0%) | 0 (0.0%) | |
| Baseline Mg—median (range) | 2 (0.9–2.6) | 2.1 (1.6– 2.5) | 0.112 |
| Cmab administration—median (range) | 9 (2–111) | 10 (1– 40) | 0.956 |
| MgO oral administration—n (%) | 44 (73.3%) | 26 (53.1%) | 0.044 |
Significance was determined using the Mann–Whitney U test and Fisher exact test. Mg, magnesium; FP, 5-fluorouracil + cisplatin; FC, 5-fluorouracil + carboplatin; Cmab, cetuximab; PTX, paclitaxel; MgO, magnesium oxide.
(a) Cumulative incidence of all-grade and (b) grade ≥2 hypomagnesemia in patients treated with cetuximab therapy with (n = 49) and without (n = 60) prophylactic Mg administrations. (c) The difference of all-grade hypomagnesemia in patients who received the FP/FC + Cmab regimen and (d) the PTX + Cmab regimen with or without prophylaxis. (e) The ratio of patients who received additional Mg administrations to maintain serum Mg levels after hypomagnesemia among those treated with the FP/FC + Cmab and (f) PTX + Cmab regimens. Significance was determined using the Gray test and Fisher exact test. ** p < 0.01. Mg, magnesium; FP, 5-fluorouracil + cisplatin; FC, 5-fluorouracil + carboplatin; Cmab, cetuximab; PTX, paclitaxel.
CDDP-induced nephrotoxicity may contribute to the exacerbation of hypomagnesemia by disturbing Mg homeostasis in the renal tubules. In patients treated with the FP + Cmab regimen, an increase in the serum creatinine levels was observed in both the non-prophylactic group (pre-treatment: 0.82 mg/dL, worst value: 1.01 mg/dL; Supplementary Fig. 3a) and prophylactic group (pre-treatment: 0.65 mg/dL, worst value: 0.74 mg/dL; Supplementary Fig. 3b). Despite the number of CDDP administrations was consistent in both groups, patients receiving Mg prophylaxis demonstrated a significant suppression of creatinine level elevations compared to those without Mg prophylaxis (Supplementary Figs. 3c, d). Furthermore, we observed no discernible fluctuations in renal function among patients treated with the PTX + Cmab regimen (Supplementary Figs. 3e–g).
Effect of Prophylactic Mg Treatment on the Risk Factor of HypomagnesemiaRisk factors for hypomagnesemia were examined in patients with and without prophylactic Mg treatment with the baseline serum Mg level, the number of Cmab administrations, and concurrent platinum treatment as covariates. In patients without prophylactic Mg, the low serum Mg level at treatment initiation (≤2.0 mg/dL) was identified as a risk factor (odds ratio: 6.03, 95% CI: 1.78–20.4, p = 0.004). In contrast, the risk factor in patients administered prophylactic Mg was the number of Cmab doses (≥10) (OR: 5.50, 95% CI: 1.52–19.87, p = 0.009) (Table 2). In ROC analysis, the number of Cmab administrations in the prophylactic Mg treatment group was significantly associated with hypomagnesemia (area under the curve: 0.727, 95% CI: 0.58–0.87, p = 0.007, cut-off value 13.5; Supplementary Fig. 4).
| Variables | Prophylactic Mg treatment (−), n = 60 | Prophylactic Mg treatment (+), n = 49 | ||||
|---|---|---|---|---|---|---|
| OR | 95% CI | p-Value | OR | 95% CI | p-value | |
| Baseline Mg | ||||||
| ≤2.0 mg/dL | 6.03 | 1.78–20.4 | 0.004 | 3.46 | 0.94–12.75 | 0.062 |
| Number of Cmab administration | ||||||
| ≥10 | 0.78 | 0.22–2.78 | 0.702 | 5.50 | 1.52–19.87 | 0.009 |
| Concurrent platinum usage | ||||||
| Yes | 0.68 | 0.19 –2.40 | 0.553 | 1.30 | 0.28–6.04 | 0.741 |
Significance was determined using logistic regression analysis. Mg, magnesium; OR, odds ratio; 95% CI, 95% confidence interval; Cmab, cetuximab.
Cmab is the first monoclonal antibody for patients with HNC, approved in 2006, and it still plays an essential role as the mainstay of treatment for locoregionally advanced, unresectable, and recurrent HNC. This study aimed to investigate the real-world incidence of Cmab-induced hypomagnesemia in patients with HNC, uncover the risk factors for its development, and scrutinize strategies to prevent this adverse event to alleviate patient burden. The results showed that all-grade hypomagnesemia occurred in 61.7% of patients, and grade ≥2 hypomagnesemia occurred in 16.7%. Concomitant radiation, chemotherapy regimens, and medications such as diuretics and PPIs did not affect the prevalence. A low serum Mg level (≤2.0 mg/dL) at pre-treatment was extracted as a risk factor for hypomagnesemia.
This study is the first to examine the preventive effect of prophylactic intravenous Mg administration. In patients treated with FP + Cmab and PTX + Cmab regimens, the cumulative incidence of hypomagnesemia was not significantly reduced by preventative Mg treatment; however, prophylactic treatment mitigated the risk of hypomagnesemia in patients with low pre-treatment Mg levels. Moreover, prophylactic Mg eliminated additional Mg administration to maintain serum Mg levels in patients treated with PTX + Cmab but not in patients treated with FP + Cmab. This result might be attributed to the difference in the prophylactic Mg doses between the two regimens. In the future, the preventive effect should be revised after the Mg doses in the FP + Cmab regimen increase, as well as the PTX + Cmab regimen. Notably, prophylactic Mg treatment in both regimens did not cause severe adverse events in this study.
The frequency of hypomagnesemia varies considerably between trials. Hypomagnesemia occurred in 18.2 and 0.5% of patients in phase II and phase III trials of Cmab coupled with radiotherapy for locoregionally advanced HNC, respectively.12,13) Additionally, hypomagnesemia occurred in 75.8 and 5.5% of patients in phase II and phase III trials of Cmab with platinum-based chemotherapy for recurrent and metastatic HNC, respectively.2,14) These differences are presumed to result from the frequency of Mg monitoring since an early retrospective study reported that serum Mg levels were non-mandatory and consistently monitored in only 20% of patients.5) In a recent study, Enokida et al. reported an overall incidence of hypomagnesemia of 50.4% in patients with HNC treated with Cmab, and a meta-analysis of patients with colorectal cancer showed a prevalence of approximately 40%, which is consistent with the results of our study.7,8,15)
Plasma Mg is primarily excreted in the urine by the glomeruli and is reabsorbed by the nephron tubules. This reabsorption occurs at rates of 10–25% in the proximal tubules, 50–70% in the thick ascending limb (TAL) of the Henle loop, and 5–10% in the distal convoluted tubule (DCT).16) Hypomagnesemia induced by Cmab is thought to involve the transient receptor potential melastatin 6 (TRPM6) channel, which is responsible for Mg reabsorption in the DCT.17) Because the activation of EGFR signaling regulates the expression of TRPM6 on the membrane, the inhibition of EGFR by Cmab decreases TRPM6 expression on the apical membrane and suppresses Mg reabsorption in the DCT.6,18)
CDDP-induced nephrotoxicity directly impairs Mg reabsorption in the TAL of the Henle loop and DCT.19,20) Given previous reports indicating a history of platinum administration as a risk factor for Cmab-induced hypomagnesemia,7) we delved into the occurrence of renal dysfunction. Results demonstrated a significant presence of platinum drug-induced renal injury. Despite the mitigating effect of prophylactic Mg administration on renal toxicity, as evidenced in a prior study,21) it did not alleviate the incidence of Cmab-induced hypomagnesemia. Collectively, our findings suggest that concomitant platinum-based drugs did not influence Cmab-induced hypomagnesemia within our study population. Additionally, loop diuretics, employed for fluid balance regulation during hydration in a CDDP-containing regimen, are known to decrease Mg reabsorption by reducing the positive transepithelial voltage that drives Mg transport in the TAL.22) However, our results indicate that loop diuretics did not contribute to Cmab-induced hypomagnesemia. These outcomes suggest that Cmab-induced hypomagnesemia depends on TRPM6-mediated Mg reabsorption at the DCT rather than at the proximal convoluted tubule or TAL of the Henle loop.
Intravenous supplementation with Mg sulfate is recommended to treat hypomagnesemia, but a systematic review reported that severe hypomagnesemia is often refractory to high-dose and frequent intravenous replacement.8) Oral administration of Mg oxide is convenient; however, its effects are inconsistent among studies, and tolerability has been unacceptable.8) Therefore, preventing the development of hypomagnesemia is preferable. We showed that prophylactic intravenous Mg administration from the initiation of Cmab treatment decreased the risk of hypomagnesemia in patients with low Mg levels without severe adverse events. Plasma Mg levels were managed without additional Mg administration, especially in patients treated with the PTX + Cmab regimen, potentially reducing the burden on the patients. This prophylactic method is considered to be an essential management strategy for the use of anti-EGFR antibodies.
This study has several limitations. Firstly, this was a single-center retrospective analysis. Despite thoroughly investigating the patient's background characteristics to account for potential influences on hypomagnesemia prevalence, unassessed confounding factors may have introduced bias due to the absence of randomization. Secondly, while the prophylactic administration of Mg showed a tendency to reduce the development of hypomagnesemia by >10%, there was no statistically significant difference in prevalence. Further research is warranted to validate the efficacy of prophylactic Mg administration, especially considering the preventive impact of the FP/FC + Cmab regimen, which should be reassessed with increased Mg supplementation to 20 mEq/week alongside the PTX + Cmab regimen. The results of multivariate analysis of risk factors suggest that the reduction in Mg reabsorption via TRPM6 extends beyond the effect of prophylaxis in patients undergoing long-term Cmab administration. Consequently, the next step involves formulating a strategy targeting TRPM6 to prevent hypomagnesemia in patients subjected to prolonged Cmab treatment.
Our results indicate that a low pre-treatment serum Mg level emerges as the only risk factor for Cmab-induced hypomagnesemia, and this risk can be effectively mitigated through prophylactic Mg sulfate administration. This preventive intervention exhibits minimal adverse events and is thus recommended for managing Cmab-induced hypomagnesemia. Despite its key role in treating HNC, the prevention of hypomagnesemia in patients undergoing long-term Cmab treatment remains an area lacking established protocols, underscoring the importance of regular monitoring of serum Mg levels and early intervention. Given that Cmab interruption due to adverse events directly impacts prognosis, the insights gleaned from our study hold significant relevance for the optimal care of HNC patients undergoing Cmab treatment.
We appreciate the physicians, medical workers, and all patients involved in this study.
This work was partly supported by the Japan Society for the Promotion of Science KAKENHI (Grant Number: 20K16078 to KS).
The authors declare no conflict of interest.
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