Research ArticleClinical Studies
Open Access

Risk Factor Analysis for Anti-epidermal Growth Factor Receptor Monoclonal Antibody-induced Problematic Skin Toxicities in Patients With Liver Metastatic Colorectal Cancer

YOSHITAKA SAITO, KAZUKI UCHIYAMA, YOH TAKEKUMA, YOSHITO KOMATSU and MITSURU SUGAWARA
In Vivo September 2024, 38 (5) 2390-2398; DOI: https://doi.org/10.21873/invivo.13706

Abstract

Background/Aim: We previously reported that patients with metastatic colorectal cancer (mCRC) and baseline liver metastasis are at a higher risk of developing grade ≥2 overall skin toxicities when treated with anti-epidermal growth factor receptor (EGFR) monoclonal antibody. This study aimed to identify additional factors associated with skin toxicities induced by anti-EGFR treatment in patients with liver metastatic CRC. Patients and Methods: Patients with liver metastatic CRC who initially received anti-EGFR monoclonal antibody-containing treatment (n=77) were retrospectively assessed. The primary endpoint was to identify the factor(s) responsible for the development of grade ≥2 overall skin toxicities. Additionally, factors for grade ≥2 rash and paronychia were evaluated. Results: The incidence of grade ≥2 overall skin symptoms, rash, and paronychia was 62.3%, 31.2%, and 28.6%, respectively. Multivariate Cox proportional hazard regression analyses revealed that age <65 years and anemia were independent baseline risk factors for grade ≥2 overall skin toxicities (adjusted hazard ratio 2.09, 95% confidence interval=1.10-3.97, p=0.02 for age; 2.36, 1.20-4.61, p=0.01 for anemia). In contrast, combination prophylaxis using systemic minocycline and corticosteroid ointment was a preventive factor (0.47, 0.25-0.88, p=0.02). Males and age <65 years were baseline risk factors for grade ≥2 rash, and combination prophylaxis was identified as a preventive factor. No factors were identified for paronychia. Conclusion: Age <65 years and anemia were identified as independent baseline risk factors. Additionally, combination prophylaxis was found to be a preventive factor against anti-EGFR monoclonal antibody-induced grade ≥2 overall skin toxicities in patients with liver metastatic CRC.

Key Words:

Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, such as panitumumab and cetuximab, are effective agents in RAS wild-type metastatic colorectal cancer (mCRC) treatment (1-10). These medicines induce several adverse effects, such as skin toxicities (acne-like rashes, paronychia, dry skin, fissures, pruritus, hyper-pigmentation, telangiectasia, and hair changes), diarrhea, and hypomagnesemia, leading to reduction in the quality of life of patients (1-8).

Skin toxicities are the most common and troublesome adverse effects caused by anti-EGFR treatment, with >80% of patients developing toxicities (11), including 20-37% having severe symptoms (2-8). There are several prophylactic strategies for skin toxicities, such as skin care using moisturizers, systemic administration of antibiotics with anti-inflammatory effects (tetracyclines or macrolides), and topical steroid ointments (mild class); however, the most suitable method remains unclear (12). We have reported that prophylactic systemic administration of antibiotics is a preventive, whereas the baseline presence of liver metastasis is a risk factor for the development of grade ≥2 overall skin toxicities in a real-world anti-EGFR mCRC treatment (12, 13). As prophylactic antibiotic administration has already been reported to be effective (14-17), we believe that its administration is essential for the prevention and attenuation of skin toxicities in anti-EGFR treatment. However, the rationale of liver metastasis as a risk factor for these symptoms remains unclear. Understanding the characteristics of high-risk populations is important to improve symptom management. Consequently, this study aimed to identify the factors associated with the development of problematic skin toxicities caused by anti-EGFR monoclonal antibodies in patients with liver metastatic CRC in a real-world setting.

Patients and Methods

Patients. Patients with liver metastatic CRC first treated with anti-EGFR monoclonal antibodies between July 2012 and September 2023 at Hokkaido University Hospital were retrospectively assessed. Baseline registry criteria were 1) age ≥18 years; 2) Eastern Cooperative Oncology Group performance status (ECOG-PS) 0-2; 3) sufficient patient information available from medical records; and 4) sufficient renal or liver function for treatment induction. Exclusion criteria for the present study were: 1) presence of problematic dermatological disease or skin toxicities due to previous chemotherapies at baseline; 2) administration of regular systemic corticosteroids; 3) non-administration of systemic minocycline from treatment initiation; 4) inability to complete two cycles of treatment due to disease progression or severe adverse effects; and 5) transfer to another hospital during treatment, as in our previous reports (12, 13). The total number of patients required was calculated as approximately 80, based on the assumption that the incidence of grade ≥2 overall skin toxicities, which were defined as primary symptoms in the previous and present studies, would be 60% in this population, and approximately 3-4 covariates were included in the multivariate Cox proportional hazard regression analysis by referring to previous reports (12, 13).

This study was approved by the Ethical Review Board for Life Science and Medical Research of Hokkaido University Hospital (approval number: 023-0287) and performed in accordance with the Declaration of Helsinki and the STROBE statement. Due to the retrospective nature of this study, the requirement for informed consent was waived by the Ethical Review Board for Life Science and Medical Research of Hokkaido University Hospital.

Treatment methods. Cetuximab infusion was administered weekly at a dose of 400 mg/m2 for 120 min at the initial administration and 250 mg/m2 for 60 min at the subsequent administration, and panitumumab 6 mg/kg was injected biweekly for 60 min (2-8). Concomitant treatment regimens were mFOLFOX6 (oxaliplatin 85 mg/m2 and levofolinate calcium 200 mg/m2 on day 1, fluorouracil 400 mg/m2 on day 1 and 2,400 mg/m2 for 46 h from day 1, every two weeks), FOLFIRI (irinotecan 150 mg/m2 and levofolinate calcium 200 mg/m2 on day 1, fluorouracil 400 mg/m2 on day 1 and 2,400 mg/m2 for 46 h from day 1, every two weeks), irinotecan (150 mg/m2, every two weeks), encorafenib (daily 300 mg once a day) with or without binimetinib (daily 45 mg twice a day), IRIS (irinotecan 100 mg/m2 on days 1 and 15 along with S-1 80 mg/m2/day on days 1-14, every four weeks), and FOLFOXIRI (oxaliplatin 85 mg/m2, irinotecan 165 mg/m2, and levofolinate calcium 200 mg/m2 on day 1, with fluorouracil 3,200 mg/m2 for 48 h from day 1, every two weeks). Anti-EGFR treatment was reduced or suspended according to the criteria adopted in previous studies (2-8, 12, 13).

Premedication consisting of a serotonin receptor 3 antagonist, dexamethasone, or aprepitant was administered depending on the emetic risk of each regimen, according to the national antiemetic guidelines (18). All patients were strongly recommended to perform skin care using a skin moisturizer at least twice daily, according to previous reports (19, 20). Prophylactic systemic minocycline 100-200 mg daily with or without topical steroid ointment twice daily (mild class, e.g., 0.25% hydrocortisone cream) was administered to all patients. Minocycline dose escalation, oral antihistamine medication, and prescription and/or strengthening of topical steroids were performed for symptom control at the physician’s discretion.

Evaluation of skin toxicities. All required information was obtained from participants’ medical records. Skin toxicities were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, by a medical team consisting of physicians, pharmacists, and nurses at every treatment visit; the worst grade of symptoms was expressed in accordance with our previous reports (12, 13).

The primary endpoint of the present study was to identify the factor(s) for the development of CTCAE grade ≥2 overall skin toxicities during all treatment cycles, which was in line with our previous studies (12, 13). Secondary endpoints were assessment of the factors associated with the development of grade ≥2 papulopustular rash and paronychia, and comparison of skin toxicities between specific patient groups.

Statistical analysis. Univariate and multivariate Cox proportional hazard regression analyses were performed to identify the independent factors associated with the development of grade ≥2 skin toxicities using the following possible covariates: sex, age, ECOG-PS score, clinical stage, primary site, body mass index, presence of anemia, thrombocytopenia, hypoalbuminemia, and liver dysfunction (CTCAE grade 1 or higher elevation of aspartate aminotransferase, alanine aminotransferase, and total bilirubin), smoking history, regular alcohol intake (≥5 days a week), and prior treatment history at baseline, treatment regimens (monotherapy or combination therapy), type of anti-EGFR monoclonal antibody, and prophylaxis using systemic minocycline and topical steroid ointment, in accordance with previous reports (12, 13, 19-22) and our clinical comprehension. Candidate variables with p-values <0.20 in the univariate analysis were included in the multivariate analysis (one candidate per 10 events). Incidence of grade ≥2 overall skin toxicities between specific patient populations was described in an intention-to-treat manner using the Kaplan-Meier method, and the differences were compared using the log-rank test.

All data analyses were performed using JMP version 16.1 statistical software (SAS Institute Japan, Tokyo, Japan). p-Values <0.05 were considered statistically significant.

Results

Patient characteristics. A total of 77 patients with liver metastatic CRC were evaluated (Figure 1). The baseline patient characteristics are described in Table I. Males accounted for 67.5% of the patients with a median age of 64 years (range=26-85 years). The median hemoglobin level was 12.2 g/dl (8.4-15.6 g/dl), and median serum albumin level was 3.8 g/dl (2.2-4.8 g/dl). Approximately 80% of participants received combination therapy with other chemotherapeutic agents. Panitumumab and cetuximab were administered to 55.8% and 44.2% of patients, respectively. Systemic minocycline dosages were 100 mg daily and 200 mg daily in 85.7% and 14.3% of patients, respectively. Topical steroid ointment prophylaxis was co-administered with 100 mg minocycline daily in 68.8% of participants.

Figure 1.
Figure 1.

Study design.

View this table:
Table I.

Patient characteristics.

Incidence and severity of skin toxicities. The incidence and severity of skin toxicities are listed in Table II. The incidence of grade ≥2 overall skin symptoms was 62.3%, with the development of at least one or more any-grade skin symptoms in all participants. Grade ≥2 papulopustular rash and paronychia occurred in 31.2% and 28.6% of the patients, respectively. The median onset time of the first grade ≥2 skin toxicity was 62 days (range=14-693 days), and that of grade ≥2 papulopustular rash and paronychia was 51 days (14-159 days) and 83 days (14-763 days), respectively. Dose reduction of anti-EGFR antibodies due to skin toxicities was confirmed in 36.4% of the patients (all reduction rates were 40.3%). The final dosages of anti-EGFR antibodies were full dose for 59.7%, 80% dose for 23.4%, and 60% dose for 16.9%, respectively.

View this table:
Table II.

Incidence and severity of skin toxicities.

Risk factor analysis of grade ≥2 skin toxicities. Multivariate analyses revealed that age <65 years and anemia were independent baseline risk factors for the development of grade ≥2 overall skin toxicities [Table III, adjusted hazard ratio 2.09, 95% confidence interval (95%CI)=1.10-3.97, p=0.02 for age and 2.36, 1.20-4.61, p=0.01 for anemia, respectively]. In contrast, the combination prophylaxis was a preventive factor (0.47, 0.25-0.88, p=0.02). With regard to grade ≥2 papulopustular rash, male sex and age <65 years were independent baseline risk factors (3.48, 1.16-10.41, p=0.03 for males and 2.73, 1.15-6.50, p=0.02 for age, respectively); combination prophylaxis was identified as a preventive factor (0.36, 0.16-0.81, p=0.01). However, no factors were identified for grade ≥2 paronychia.

View this table:
Table III.

Univariate and multivariate analyses of risk factors for grade ≥2 overall skin toxicities, papulopustular rash, and paronychia.

Prophylactic efficacy of combination prophylaxis in higher-risk populations. Additionally, we evaluated whether combination prophylaxis is superior to antibiotic monotherapy in high-risk populations (Figure 2). Patients with baseline anemia who received combination therapy had significantly better outcomes than those without the treatment in the development of grade ≥2 overall skin toxicities [median onset time (95%CI)=126 (57-693) and 49 (38-64) days in combination therapy and systemic minocycline monotherapy, respectively, p=0.004, Figure 2A]; however, younger patients did not achieve the benefits [109 (69-152) and 70 (40-159) days, respectively, p=0.58, Figure 2B].

Figure 2.
Figure 2.

Kaplan-Meier curves for the development of grade ≥2 overall skin toxicities between patients treated with and without prophylactic combination medication in those (A) with baseline anemia and (B) younger than 65 years.

Discussion

Skin toxicities are problematic adverse effects of anti-EGFR treatments and most treatments are administered in outpatient settings. There are several management strategies to prevent or treat these symptoms; however, at times, there are difficulties in dealing with them. It is important to recognize the characteristics of the high-risk population. Therefore, we aimed to further evaluate the factors for the development of problematic skin toxicities caused by anti-EGFR monoclonal antibodies in patients with liver metastatic CRC in a real-world setting.

Age <65 years and anemia were suggested as baseline risk factors for grade ≥2 overall skin toxicities. In contrast, combination prophylaxis using systemic minocycline and topical steroid ointments was identified as a preventive factor against its development. In addition, younger age and male sex were identified as risk factors, and combination prophylaxis was revealed as a preventive factor for grade ≥2 papulopustular rash although no factors were identified for paronychia. To the best of our knowledge, this is the first study to evaluate the factors associated with problematic skin toxicities following anti-EGFR treatment in patients with liver metastatic CRC, a high-risk population.

Younger age was suggested as a risk factor for severe rash caused by anti-EGFR monoclonal antibodies in a previous report, although overall skin toxicities were not assessed (21). Reenstra et al. suggested that a decrease in EGFR expression in fibroblasts with age leads to fewer cutaneous targets in older patients, resulting in more skin toxicities in younger patients (21, 23).

Anemia was first identified as a risk factor, although it was not suggested in an all-population analysis (12). One hypothetical mechanism is the involvement of interleukin (IL). IL-8 secretion by fibroblasts and keratinocytes activates neutrophil migration in cutaneous tissues (24-26). In addition, Bangsgaard et al. reported that IL-8 neutralization prevents the adverse dermatological effects of anti-EGFR agents (27). Thus, we speculated that patients with liver metastatic CRC with elevated serum IL-8 levels (28-30) are a high-risk population for anti-EGFR antibody-induced skin toxicities compared to those without (12, 13). Anemia is strongly associated with hypoxia, and previous studies showed that hypoxia induces hypoxia-inducible factor-1 (HIF-1) (31-33). In addition, Fei et al. have reported that IL-8 is regulated by hypoxia-induced HIF-1α (34). Consequently, further IL-8 elevation due to hypoxia in patients with anemia may have affected the results; however, further studies are needed to elucidate these mechanisms.

Male sex has also been suggested as a risk factor for rashes (22). Raimondi et al. surmised that the difference in the hormonal milieu affected the results, as androgens and estrogens interact with EGFR, particularly in rash, but not paronychia (12, 22).

Combination prophylaxis was identified as a preventive factor for overall skin toxicities in the present population, although it has not been suggested as a factor in the entire patient population (12, 13). Skin disorders following anti-EGFR treatment appear two days after the first administration (35, 36). Skin inflammation caused by inhibition of the EGFR pathway is one of the main mechanisms of skin toxicity (37, 38). Therefore, prophylactic administration of anti-inflammatory agents, such as antibiotics (tetracyclines or macrolides) or corticosteroids, is important to manage skin toxicities by anti-EGFR agents (12, 13). However, the prophylactic use of topical steroids imposes a heavy burden on patients. We reported that preventive topical steroid administration can be adjusted or discontinued depending on the severity of the papulopustular rash, as its addition only attenuates the papulopustular rash, which becomes less severe over time (39), in the all-patient population (12, 13). However, in patients with liver metastatic CRC, particularly those with baseline anemia, topical steroids should possibly be continued during all treatment periods, considering the broad onset of overall skin toxicities.

Patient education is one of the most important aspects for healthcare professionals, as patients with high medication literacy exhibit milder skin toxicities during EGFR-tyrosine kinase inhibitor treatment (40). Lacouture et al. also emphasized the importance of a multidisciplinary medical team consisting of physicians, pharmacists, and nurses for the management of anti-EGFR treatment-induced skin toxicities (41). Therefore, medical teams should educate and encourage patients to manage skin toxicities.

Study limitations. First, it was a retrospective study and included a relatively small patient population from a single institution. Second, considering the retrospective nature of the present study, we adopted an objective assessment by medical personnel. However, as skin toxicities induce both bodily and emotional distress (36), a patient-subjective assessment will provide additional clinical significance. Third, we were unable to adequately evaluate adherence to preemptive treatment, although we attempted to confirm and encourage patients at every visit. Fourth, oncologists tend to overestimate the severity of skin toxicities compared with dermatologists (20), which might have affected the results. Finally, we did not evaluate the patients’ genetic backgrounds or IL-8 levels. Therefore, our preliminary findings should be validated in future studies.

Conclusion

The present study suggested that age <65 years and anemia were independent baseline risk factors and combination prophylaxis was a preventive factor for the development of grade ≥2 overall skin toxicities caused by anti-EGFR monoclonal antibodies in patients with liver metastatic CRC. Appropriate management of skin toxicities is important for less onerous anti-EGFR treatments; therefore, further studies on treatment strategies and approaches to the patients by a medical team are required for better symptom management.

Footnotes

  • Authors’ Contributions

    Participated in research design: YS, KU, and YK. Conducted experiments: YS. Performed data analysis: YS. Drafting of the manuscript: YS. All Authors have read and approved the manuscript.

  • Funding

    The Authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

  • Conflicts of Interest

    YS, KU, YT, and MS have no conflicts of interest. YK reports receiving grants and personal fees from Ono, TAIHO, CHUGAI, Eli Lilly, Yakult, Bristol-Myers, Merck, Takeda, Novartis, Bayer, and Daiichi-Sankyo, and grants from Iqvia outside the submitted work.

  • Received May 7, 2024.
  • Revision received May 31, 2024.
  • Accepted June 3, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Risk Factor Analysis for Anti-epidermal Growth Factor Receptor Monoclonal Antibody-induced Problematic Skin Toxicities in Patients With Liver Metastatic Colorectal Cancer
YOSHITAKA SAITO, KAZUKI UCHIYAMA, YOH TAKEKUMA, YOSHITO KOMATSU, MITSURU SUGAWARA
In Vivo Sep 2024, 38 (5) 2390-2398; DOI: 10.21873/invivo.13706
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