Evaluation of the additional prophylactic effect of topical steroid ointment to systemic minocycline against anti-epidermal growth factor antibody-induced skin toxicities in metastatic colorectal cancer treatment

doi:10.21203/rs.3.rs-3244177/v1

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Research Article

Evaluation of the additional prophylactic effect of topical steroid ointment to systemic minocycline against anti-epidermal growth factor antibody-induced skin toxicities in metastatic colorectal cancer treatment

https://doi.org/10.21203/rs.3.rs-3244177/v1

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published 06 Dec, 2023

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Background

Anti-epidermal growth factor receptor (EGFR) antibodies often cause skin toxicities. Preemptive skin treatments using systemic antibiotics with or without topical steroid are reportedly effective although the most suitable method remains unclear. This study aimed to determine whether combination prophylaxis using systemic minocycline and topical steroid is superior to minocycline alone in a real-world metastatic colorectal cancer (mCRC) treatment.

Methods

Patients with mCRC (n = 87) who received anti-EGFR monoclonal antibodies were retrospectively assessed. The primary objective was to compare the incidence of grade ≥ 2 overall skin toxicities during all treatment periods between the two groups: the control group receiving prophylactic minocycline 100 mg/day, and the combination prophylaxis group receiving minocycline 100 mg/day + topical steroid. The incidence of each skin symptom was also evaluated.

Results

The incidence of grade ≥ 2 overall skin toxicities was 65.2% in the control and 56.9% in the combination groups, with no significant difference (P = 0.62). Similarly, the incidence of grade ≥ 2 dry skin, fissures, paronychia, and pruritus did not significantly differ. In addition, incidence of all-grade skin toxicities was not different. However, the incidence of grade ≥ 2 rashes was significantly lower in the combination group (23.1% vs. 47.8%, P = 0.03). Propensity score-matched analysis supported these results. Multivariate logistic regression analysis showed no significant association between combination prophylaxis and grade ≥ 2 overall skin toxicities, but it did show a reduction in grade ≥ 2 rashes.

Conclusion

Adding topical steroids to systemic minocycline did not mitigate grade ≥ 2 overall skin toxicities induced by anti-EGFR antibodies; however, it significantly improved rashes.

anti-epidermal growth factor receptor monoclonal antibody

skin toxicity

minocycline

topical steroid ointment

rash

combination

Anti-epidermal growth factor receptor (EGFR) antibodies such as panitumumab and cetuximab are one of the most effective treatments for RAS wild metastatic colorectal cancer (mCRC) [1]. However, as EGFR-signaling plays a critical role in epidermal physiology, skin toxicities such as papulopustular rash (acne-like), paronychia, dry skin, fissures, pruritus, hyperpigmentation, and hair changes appear in more than 80% of the administered patients [2], including 20–37% of severe cases [3–7]. These symptoms frequently lead to dose reduction, interruption, and discontinuation of the treatment. In addition, the development of grade ≥ 2 skin toxicities is reportedly associated with better treatment efficacy [8]. Consequently, skin toxicity management is necessary to maintain a patient’s quality of life and provide effective mCRC treatment.

Preemptive skin treatment using systemic antibiotics with or without topical steroid ointment is reportedly effective for anti-EGFR treatment-induced skin toxicities [9–13]. However, it is unknown whether combination therapy is superior to antibiotic monotherapy. We have found that prophylactic administration of antibiotics such as minocycline and clarithromycin is significantly associated with grade ≥ 2 overall skin toxicity reduction, although the addition of preemptive steroid ointment is not related; but combination prophylaxis was significantly related to rash reduction [14]. However, the dosage of minocycline varied and clarithromycin at a dosage of 400 mg/day was also administered in this study. Additionally, all patients administered combination prophylaxis received 100 mg/day minocycline in the study [14], suggesting that our previous evaluation regarding combination prophylaxis may be insufficient. Regular prophylactic steroid ointment implementation is a heavy burden to the patients; therefore, we aimed to reveal the significance of combination prophylaxis using systemic minocycline and topical steroid against anti-EGFR antibody-induced skin toxicities in a real-world mCRC treatment.

1. Patients

Patients with mCRC first receiving anti-EGFR monoclonal antibody-containing treatment from July 2012 to November 2022 at Hokkaido University Hospital were retrospectively assessed. Baseline registry criteria were (1) age ≥ 18 years, (2) Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0–2, (3) adequate liver or renal function for treatment induction, and (4) sufficient patient information available from medical records, which was in line with our previous report [14]. Patients with baseline uncontrolled cutaneous symptoms or regularly receiving systemic corticosteroids, those who could not complete at least two treatment cycles, and those who transferred to another hospital during the treatment were excluded from this study and our previous analysis [14]. The patient population included in this study was extracted from our previous evaluation [14]. The patients were divided into two groups: a control group consisting of patients who received prophylactic systemic minocycline at a dose of 100 mg per day and practiced regular skin moisturization at least twice a day from January 2013 to September 2022, and a combination group who underwent prophylaxis using topical steroid ointment (for example, 0.25% hydrocortisone cream) applied twice daily on the face, hands, feet, back, and chest, and daily systemic minocycline at 100 mg, in addition to adhering to usual skincare routines based on previous reports [12, 13] from July 2012 to November 2022. Patients were strongly encouraged to continue these prophylactic measures, and their adherence was confirmed by physicians and pharmacists at every treatment visit throughout the treatment periods.

This study was approved by the Ethical Review Board for Life Science and Medical Research of Hokkaido University Hospital (approval number: 023–0052) and was conducted in accordance with the Declaration of Helsinki and the STROBE statement. Given the retrospective nature of the study, the requirement for informed consent from the participants was waived by the Ethical Review Board for Life Science and Medical Research of Hokkaido University Hospital.

2. Treatment methods

Panitumumab 6 mg/kg was intravenously administered for 60 min biweekly, and cetuximab infusion at a dose of 400 mg/m² for 120 min at the first administration followed by weekly 250 mg/m² for 60 min was dosed [3–7, 15]. FOLFIRI (irinotecan 150–180 mg/m² and levofolinate calcium 200 mg/m² on day 1, and fluorouracil 400 mg/m² on day 1 and 2,400 mg/m² for 46 h from day 1, every two weeks), mFOLFOX6 (oxaliplatin 85 mg/m² and levofolinate calcium 200 mg/m² on day 1, and fluorouracil 400 mg/m² on day 1 and 2,400 mg/m² for 46 h from day 1, every two weeks), FOLFOXIRI (irinotecan 165 mg/m², oxaliplatin 85 mg/m², and levofolinate calcium 200 mg/m² on day 1, fluorouracil 3,200 mg/m² for 48 h from day 1, every two weeks), IRIS (irinotecan 100 mg/m² on days 1 and 15 with S-1 80 mg/m²/day on days 1–14, every four weeks), encorafenib (daily 300 mg once a day) with binimetinib (daily 45 mg twice a day), or irinotecan (150–180 mg/m², every two weeks) was co-administered with anti-EGFR agents. Anti-EGFR treatment was managed according to the criteria adopted in previous reports [3–7, 15].

Aprepitant, serotonin receptor 3 antagonists, and systemic dexamethasone were co-administered depending on the emetic risk of each regimen according to national antiemetic guidelines [16]. Minocycline dose adjustments, oral antihistamine administration, and dosing or strengthening of topical steroid ointment were implemented for symptom control at the physician’s discretion.

3. Survey and evaluation of skin toxicities

Necessary information was obtained from the medical records of the enrolled patients. Skin toxicities were evaluated 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 visit, with the most severe grade recorded.

The primary objective of this study was to evaluate the incidence of CTCAE grade ≥ 2 overall skin toxicities during all treatment cycles in the two groups. We focused on grade ≥ 2 symptoms as they are deemed clinically significant [14]. Secondary endpoints included assessing the incidence of grade ≥ 2 rash, dry skin, skin fissure, paronychia, and pruritus, and all-grade skin symptoms, between both groups. In addition, a risk factor analysis was performed to identify factor(s) associated with the development of grade ≥ 2 skin symptoms. Furthermore, propensity score-matching was performed to adjust the baseline factors between the groups, and matched data were additionally analyzed to evaluate the robustness of the all-population analysis.

4. Statistical analysis

Differences in baseline clinical characteristics between the control and combination groups were evaluated using Fisher's exact probability test for categorical variables and the Mann-Whitney U test for continuous variables. The incidence of skin toxicities was compared between the two groups using Fisher's exact probability test. Univariate and multivariate logistic regression analyses were performed to identify the independent risk factor(s) for grade ≥ 2 skin toxicity development. Possible baseline covariates included sex, age, ECOG-PS, recurrence setting, primary site (right of left), body surface area (BSA), body mass index (BMI), presence of liver metastasis, hypoalbuminemia, liver dysfunction (grade ≥ 1 aspartate aminotransferase, alanine aminotransferase, and total bilirubin elevation), renal dysfunction (creatinine clearance calculated by Cockroft-Gault formula of < 60 mL/min), smoking history, regular alcohol intake (≥ 5 days in a week), prior treatment history, chemotherapeutic treatment regimen (anti-EGFR antibody monotherapy or combination therapy), type of anti-EGFR monoclonal antibody, and prophylactic combination of systemic minocycline and topical steroid ointment, by reference to previous reports [12–14, 17, 18]. Variables that demonstrated potential associations with the development of skin toxicity, with P < 0.20 in the univariate logistic regression analysis, and skin prophylaxis methods were included in the multivariable model. Propensity score-matching was performed using the following baseline variables: sex, age, ECOG-PS, primary site, BMI, treatment line, presence of liver metastasis, liver dysfunction, renal dysfunction, and the chemotherapeutic treatment regimen (anti-EGFR antibody monotherapy or combination therapy). To reduce bias arising from these potential confounding factors, 1:1 matching (without replacement) in the two groups was achieved using the nearest neighbor method with a 0.20- width caliper of the standard deviation of the logit of propensity scores.

All analyses were performed using JMP version 16.1 statistical software (SAS Institute Japan, Tokyo, Japan). P-values less than 0.05 were considered statistically significant.

Patient characteristics

Overall, this study evaluated 87 patients with mCRC, with 22 patients in the control group and 65 patients in the combination group (Figure 1). The baseline patient characteristics are shown in Table 1. There were no differences between the two groups regarding sex, age, ECOG-PS, recurrence, liver metastasis presence, BSA, BMI, serum albumin levels, liver dysfunction, creatinine clearance, smoking history, regular alcohol intake, treatment line, treatment regimens, and type of anti-EGFR antibody in the patient population. However, a significantly higher proportion of patients in the control group were diagnosed with right-sided mCRC. In contrast, there were no differences observed in the propensity score-matched population.

Incidence and severity of skin toxicities

Figure 2 shows the incidence of grade ≥2 and all-grade skin toxicities during all anti-EGFR treatments. The incidence of grade ≥2 overall skin toxicities in the all patient population was 63.6% in the control group and 56.9% in the combination group, respectively, with no significant difference observed (P=0.63, Figure 2A). Similarly, there were no significant differences in the incidence of grade ≥2 dry skin, fissures, paronychia, and pruritus between the two groups. In addition, the incidence of all-grade skin toxicities was not different (Figure 2B). However, the incidence of grade ≥2 rash was significantly lower in the combination group compared to the control group (23.1% vs. 50.0%, P=0.03). These results were consistent in the propensity score-matched population (Figure 2C and 2D).

There was no significant difference in dose reduction of anti-EGFR antibodies between the two groups in the overall patient population (40.9% in the control group patients and 38.5% in the combination group patients, respectively, P=1.00). Additionally, dose reduction, due to skin toxicities, was performed in 40.9% of the controls and 33.9% of the combination group, respectively, which was not significantly different (P=0.61). The final anti-EGFR antibody dosage was full dose for 54.6% in the control group and 61.5% in the combination group, 80% dosage for 22.7% and 23.1%, and 60% dose for 22.7% and 15.4%, respectively, without significant differences (P=0.69). Onset time of the first grade ≥2 overall skin symptoms and the rash was not significantly different (median with range: 47 with 14–160 days in the control group and 70 with 14–693 days in the combination group, P=0.20, for overall skin toxicities; 46 with 14–160 days and 49 with 14–88 days, P=0.82, for rash). These results were also obtained in the propensity score-matched population (data not shown).

Risk factor analysis of grade ≥2 skin toxicities

The results of univariate and multivariate logistic regression analyses are shown in Table 2. Liver metastasis presence was found as a risk factor for the development of grade ≥2 overall skin toxicities. However, combination prophylaxis was not associated as well as our previous report (adjusted odds ratio 3.34, 95% confidence interval (CI) 1.30–8.57, P=0.01 for liver metastasis; 0.69, 0.24–1.95, P=0.48 for combination prophylaxis, Table 2A) [14]. In contrast, combination prophylaxis using systemic minocycline and topical steroid ointment was suggested as an independent preventive factor for grade ≥2 rash development (0.32, 0.11–0.92, P=0.03), although male sex was identified as a risk factor for its development (3.11, 1.01–9.57, P=0.048, Table 2B). However, no factors were found to be associated with grade ≥2 paronychia. It is important to note that liver metastasis was not included in the analysis as none of the patients without metastasis experienced the symptom (Table 2C).

Skin toxicities are one of the most attention-requiring adverse effects caused by anti-EGFR treatment, although the most suitable prophylaxis remains unclear. Administration of systemic antibiotics such as tetracyclines or macrolides with or without topical steroid ointment is reportedly effective for skin toxicity management, particularly as prophylaxis [9–14]. In this study, we aimed to reveal the additional effect of topical steroid ointment combined with daily 100 mg of systemic minocycline against anti-EGFR antibody-induced skin toxicities in a real-world mCRC treatment.

The study findings showed that adding steroid ointment did not effectively reduce grade ≥ 2 overall skin toxicities compared to minocycline alone. However, its addition significantly reduced the incidence of grade ≥ 2 rash. These results align with our previous report [14]. In this study, we integrated the type and administration methods of antibiotics, first evaluating the additional effect of topical steroid ointment on systemic minocycline prophylaxis. It has been reported that skin toxicities typically appear within two days of initiating anti-EGFR treatment, suggesting that reactive management may be too late and emphasizing the potential efficacy of preemptive skin treatment [19, 20]. As the onset time of grade ≥ 2 rashes did not differ between the groups, additional topical steroids only reduced their incidence without delaying their appearance. The action of minocycline 100 mg once a day is considered not long, and its blood concentration might not be enough for skin toxicity prevention. However, our previous analysis demonstrated a significant association between systemic antibiotic administration and the reduction of grade ≥ 2 overall skin toxicities [14]. We believe that the early onset of acne-like rash was attenuated by topical steroid ointment addition owing to insufficient efficacy of minocycline alone, although the rash becomes less severe over time [21]. In contrast, other skin symptoms such as fissures and paronychia appear in more localized regions with more intense inflammation and pain than the rash. We hypothesize that prophylaxis using mild steroid ointment, such as hydrocortisone cream may be insufficient for symptom prevention due to the strong inflammatory nature of the symptoms. Consequently, our results suggest the use of preemptive topical steroid ointment (mild class) to mitigate specifically early-onset rash. However, the administration of topical steroids should be discontinued or adjusted depending on the severity of the rash, considering the potential burden on the patients. Conversely, systemic antibiotics should be continued during all treatment periods, as described in previous reports [9, 14]. Further evaluation regarding the best minocycline dosage and strength of topical steroid ointment is required.

In an additional analysis, liver metastasis was identified as an independent risk factor for overall grade ≥ 2 skin toxicities, and male sex as a risk factor for grade ≥ 2 rash. Liver metastasis was also detected as a factor in our previous study [前の]. However, its mechanism remains unclear, although we speculated that higher serum IL-8 levels in mCRC patients with liver metastasis may be associated with its development [前の]. Men have already been reported to have a higher risk of developing a rash [17, 18]. Raimondi et al. speculated that the difference in hormonal milieu affects the results as androgens and estrogens display a remarkable interaction with EGFR [18]. Consequently, we should carefully manage skin toxicities in these patients, and further evaluation to elucidate the rationales is needed.

There are several limitations to consider in this study. First, this study was conducted retrospectively with a small patient population from a single institution. Second, we could not fully evaluate the adherence to topical ointment, including moisturizers, although we made efforts to confirm and educate patients during each visit. Third, as mentioned in our previous report, oncologists tend to overestimate the severity of skin toxicities compared to dermatologists, which may have resulted in an overestimation of the symptoms’ severity [13, 14]. Fourth, we did not assess the genetic backgrounds of the participants. However, previous reports suggested that EGFR polymorphisms, other genomic mutations, and some biomarkers have predictive values for developing anti-EGFR antibody-induced skin toxicities [22–26]. Finally, in the overall patient population, the control group had a higher proportion of right-sided diagnoses. However, it was not associated with grade ≥ 2 skin toxicity development in the logistic analysis, and similar results were obtained in a propensity score-matched population. Assessment of the well-balanced population was advisable. Therefore, our preliminary outcomes should be confirmed in future studies.

In conclusion, our study revealed that additional topical steroid ointment to systemic minocycline does not attenuate anti-EGFR antibody-induced overall skin toxicities. However, it significantly ameliorated rash development. Therefore, further evaluation for the best managing strategy focusing on prophylactic periods is required.

Funding: None.

Conflict of Interest: YS, KU, YT, and MS have no conflicts of interest. YK reports grants and personal fees from Ono, Taiho, Chugai, Eli Lilly, Daiichi Sankyo, Nippon Kayaku, and MSD; personal fees from Bayer and Yakult; and grants from IQVIA, Astellas, Nippon Zoki, Shionogi, EPS, Eisai, and National Cancer Center outside the submitted work.

Ethical approval: All procedures performed in this study involving human participants were performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. For this type of study, the need for formal consent was waived by the Ethical Review Board for Life Science and Medical Research at Hokkaido University Hospital.

Consent to participate: Formal consent was not required for this type of study.

Consent for publication: Not applicable.

Availability of data and materials: The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Authors' contributions:

Research design: YS, KU, and YK; Conducted experiments: YS; Data analysis: YS; Drafting of the manuscript: YS. All authors have read and approved the manuscript.

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Table 1 Patient characteristics

	All-patient analysis			Propensity-matched analysis
	Control group (n=22)	Combination group (n=65)	P-value	Control group (n=18)	Combination group (n=18)	P-value
Sex (male/female)	16/6	39/26	0.32	12/6	13/5	1.00
Age (median, range)	62 (20–85)	62 (19–80)	0.93	61 (20–77)	63 (19–80)	0.30
Performance status (ECOG) 0-1/2	21/1	63/2	1.00	17/1	18/0	1.00
Primary site (n) Sigmoid colon Rectum Transverse colon Ascending colon Descending colon Cecum Right/left	10 3 5 2 0 2 9/13	23 28 4 4 5 1 9/56	0.01*	9 2 4 1 0 2 7/11	4 7 2 3 1 1 6/12	1.00
Recurrence (n, %)	8 (36.4%)	18 (27.7%)	0.44	5 (27.8%)	8 (44.4%)	0.49
Liver metastasis presence (n, %)	14 (63.6%)	45 (69.2%)	0.79	12 (66.7%)	12 (66.7%)	1.00
BSA (m²) (median, range)	1.64 (1.24–2.12)	1.65 (1.28–2.18)	0.86	1.64 (1.24–2.12)	1.62 (1.30–2.06)	0.89
BMI (kg/m²) (median, range)	22.85 (15.42–28.03)	22.59 (15.49–34.89)	0.66	23.03 (15.42–27.43)	21.65 (18.63–34.89)	0.96
Albumin (g/dL) (median, range)	3.8 (2.5–4.7)	3.8 (2.2–4.8)	0.84	3.8 (2.5–4.7)	4.0 (2.7–4.8)	0.40
Liver dysfunction (n, %)	9 (40.9%)	20 (30.8%)	0.29	8 (44.4%)	7 (38.9%)	1.00
CCr (mL/min) (median, range)	84.6 (40.6–148.4)	82.9 (23.8–204.2)	0.79	85.0 (40.6–148.4)	79.1 (23.8–154.2)	0.62
Smoking history (Former or Current) (n, %) Current smoker Unknown	11 (50.0%) 2 (9.1%) 0 (0%)	41 (64.1%) 9 (14.1%) 1 (1.5%)	0.31 0.72	10 (55.6%) 2 (11.1%) 0 (0%)	12 (70.6%) 1 (5.9%) 1 (1%)	0.49 1.00
Alcohol intake (≥5 days in a week) (n, %) Unknown	9 (40.9%) 0 (0%)	24 (37.5%) 1 (1.5%)	0.80	6 (33.3%) 0 (0%)	6 (33.3%) 0 (0%)	1.00
Treatment line (n, %) 1st line 2nd or later line	7 (31.8%) 15 (68.2%)	32 (49.2%) 33 (50.8%)	0.22	6 (33.3%) 12 (66.7%)	3 (16.7%) 15 (83.3%)	0.44
EGFR-containing treatment regimens (n, %) Monotherapy Combination therapy	5 (22.7%) 17 (77.3%)	10 (15.4%) 55 (84.6%)	0.52	4 (22.2%) 14 (77.8%)	5 (27.8%) 13 (72.2%)	1.00
Type of EGFR antibody (n, %) Panitumumab Cetuximab	10 (45.5%) 12 (54.6%)	36 (55.4%) 29 (44.6%)	0.32	7 (38.9%) 11 (61.1%)	9 (50.0%) 9 (50.0%)	0.74
Treatment regimens (n, %) Panitumumab + mFOLFOX6 Cetuximab + irinotecan Panitumumab + irinotecan Cetuximab + FOLFIRI Cetuximab monotherapy Panitumumab monotherapy Cetuximab + mFOLFOX6 Cetuximab + encorafenib + binimetinib Panitumumab + FOLFIRI Cetuximab + irinotecan + S-1 Cetuximab + FOLFOXIRI	6 (27.3%) 5 (22.7%) 1 (4.5%) 0 (0%) 3 (13.6%) 2 (9.1%) 0 (0%) 3 (13.6%) 1 (4.5%) 1 (4.5%) 0 (0%)	22 (33.8%) 6 (9.2%) 9 (13.8%) 9 (13.8%) 6 (9.2%) 4 (6.2%) 5 (7.7%) 2 (3.1%) 1 (1.5%) 0 (0%) 1 (1.5%)		6 (33.3%) 5 (27.8%) 0 (0%) 0 (0%) 3 (16.7%) 1 (5.6%) 0 (0%) 2 (11.1%) 0 (0%) 1 (5.6%) 0 (0%)	3 (16.7%) 1 (5.6%) 3 (16.7%) 3 (16.7%) 2 (11.1%) 3 (16.7%) 2 (11.1%) 1 (5.6%) 0 (0%) 0 (0%) 0 (0%)

^*P<0.05

ECOG, Eastern Cooperative Oncology Group; BSA, body surface area; BMI, body mass index; CCr, creatinine clearance; EGFR, epidermal growth factor receptor; mFOLFOX6, oxaliplatin 85 mg/m² and levofolinate calcium 200 mg/m² on day 1, and fluorouracil 400 mg/m² on day 1 and 2,400 mg/m² for 46 h from day 1, every two weeks; FOLFIRI, irinotecan 150–180 mg/m² and levofolinate calcium 200 mg/m² on day 1, and fluorouracil 400 mg/m² on day 1 and 2,400 mg/m² for 46 h from day 1, every two weeks; FOLFOXIRI, oxaliplatin 85 mg/m², irinotecan 165 mg/m², and levofolinate calcium 200 mg/m² on day 1, and fluorouracil 3,200 mg/m² for 48 h from day 1, every two weeks

Liver dysfunction: grade 1 or higher aspartate aminotransferase, alanine aminotransferase, or total bilirubin elevation.

Table 2 Univariate and multivariate analyses of risk factors for grade ≥2 (A) all skin toxicities, (B) rash, and (C) paronychia development

Univariate analysis

Multivariate analysis

(A)

Odds ratio (95% CI)

P-value

Odds ratio (95% CI)

P-value

Sex

Male/Female

0.95 (0.39–2.31)

0.91

Excluded

Age (years)

≥65/<65

0.85 (0.36–2.00)

0.71

Excluded

Performance status (ECOG)

2/0 or 1

1.43 (0.12–16.38)

0.77

Excluded

Recurrence setting

Yes/No

0.76 (0.30–1.91)

0.56

Excluded

Primary site

Right/Left

1.14 (0.39–3.29)

0.81

Excluded

BSA (m²)

≥1.6/<1.6

0.56 (0.23–1.38)

0.21

Excluded

BMI (kg/m²)

≥25.0/<25.0

1.05 (0.39–2.82)

0.92

Excluded

Liver metastasis

Present/Absent

3.26 (1.28–8.28)

0.01*

3.34 (1.30–8.57)

0.01*

Hypoalbuminemia

Present/Absent

0.52 (0.19–1.43)

0.20

Excluded

Liver dysfunction

Present/Absent

0.64 (0.26–1.59)

0.34

Excluded

Renal dysfunction

Present/Absent

0.55 (0.17–1.81)

0.33

Excluded

Smoking history

Current or former/Never

0.69 (0.28–1.68)

0.41

Excluded

Alcohol intake (≥5 days in a week)

Present/Absent

1.09 (0.45–2.65)

0.85

Excluded

Prior treatment history

Present/Absent

0.97 (0.41–2.30)

0.95

Excluded

EGFR-containing treatment regimens Combination therapy/Monotherapy

1.30 (0.42–3.97)

0.65

Excluded

Type of EGFR monoclonal antibody

Panitumumab/Cetuximab

1.22 (0.52–2.86)

0.65

Excluded

Prophylactic minocycline and steroid ointment

Present/Absent

0.76 (0.28–2.05)

0.58

0.69 (0.24–1.95)

0.48

Univariate analysis

Multivariate analysis

(B)

Odds ratio (95% CI)

P-value

Odds ratio (95% CI)

P-value

Sex

Male/Female

3.33 (1.11–10.00)

0.03*

3.11 (1.01–9.57)

0.048*

Age (years)

≥65/<65

0.69 (0.27–1.76)

0.44

Excluded

Performance status (ECOG)

2/0 or 1

Unable to calculate

Excluded

Recurrence setting

Yes/No

0.81 (0.29–2.26)

0.69

Excluded

Primary site

Right/Left

1.22 (0.40–3.71)

0.72

Excluded

BSA (m²)

≥1.6/<1.6

1.91 (0.70–5.24)

0.21

Excluded

BMI (kg/m²)

≥25.0/<25.0

1.58 (0.56–4.43)

0.38

Excluded

Liver metastasis

Present/Absent

1.43 (0.52–3.93)

0.49

Excluded

Hypoalbuminemia

Present/Absent

0.64 (0.24–1.75)

0.39

Excluded

Liver dysfunction

Present/Absent

0.97 (0.37–2.56)

0.95

Excluded

Renal dysfunction

Present/Absent

0.38 (0.08–1.85)

0.23

Excluded

Smoking history

Current or former/Never

1.35 (0.52–3.51)

0.54

Excluded

Alcohol intake (≥5 days in a week)

Present/Absent

1.59 (0.62–4.06)

0.33

Excluded

Prior treatment history

Present/Absent

0.92 (0.37–2.33)

0.87

Excluded

EGFR-containing treatment regimens Combination therapy/Monotherapy

0.58 (0.18–1.83)

0.35

Excluded

Type of EGFR monoclonal antibody

Panitumumab/Cetuximab

1.06 (0.42–2.65)

0.91

Excluded

Prophylactic minocycline and steroid ointment

Present/Absent

0.30 (0.11–0.83)

0.02*

0.32 (0.11–0.92)

0.03*

Univariate analysis

Multivariate analysis

(C)

Odds ratio (95% CI)

P-value

Odds ratio (95% CI)

P-value

Sex

Male/Female

0.59 (0.20–1.72)

0.33

Excluded

Age (years)

≥65/<65

2.02 (0.69–5.93)

0.20

Excluded

Performance status (ECOG)

2/0 or 1

Unable to calculate

Excluded

Recurrence setting

Yes/No

0.44 (0.11–1.68)

0.23

Excluded

Primary site

Right/Left

0.45 (0.09–2.18)

0.32

Excluded

BSA (m²)

≥1.6/<1.6

0.56 (0.19–1.66)

0.29

Excluded

BMI (kg/m²)

≥25.0/<25.0

1.42 (0.43–4.66)

0.57

Excluded

Liver metastasis

Present/Absent

Unable to calculate

Excluded

Hypoalbuminemia

Present/Absent

0.66 (0.21–2.05)

0.47

Excluded

Liver dysfunction

Present/Absent

0.76 (0.24–2.43)

0.65

Excluded

Renal dysfunction

Present/Absent

0.72 (0.14–3.58)

0.68

Excluded

Smoking history

Current or former/Never

0.92 (0.31–2.70)

0.88

Excluded

Alcohol intake (≥5 days in a week)

Present/Absent

0.42 (0.13–1.44)

0.17

0.42 (0.12–1.42)

0.16

Prior treatment history

Present/Absent

0.89 (0.31–2.59)

0.84

Excluded

EGFR-containing treatment regimens Combination therapy/Monotherapy

1.71 (0.35–8.42)

0.51

Excluded

Type of EGFR monoclonal antibody

Panitumumab/Cetuximab

1.00 (0.35–2.90)

1.00

Excluded

Prophylactic minocycline and steroid ointment

Present/Absent

0.77 (0.24–2.50)

0.66

0.76 (0.23–2.51)

0.65

^*P<0.05

ECOG, Eastern Cooperative Oncology Group; BSA, body surface area; BMI, body mass index; EGFR, epidermal growth factor receptor

Liver dysfunction: grade ≥1 aspartate aminotransferase, alanine aminotransferase, and total bilirubin levels

Renal dysfunction: creatinine clearance of less than 60 mL/min.

No competing interests reported.

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Evaluation of the additional prophylactic effect of topical steroid ointment to systemic minocycline against anti-epidermal growth factor antibody-induced skin toxicities in metastatic colorectal cancer treatment

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