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Factors Influencing the Appearance of Oxaliplatin-Induced Allergy
2017 Volume 40 Issue 12 Pages 2105-2109
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2017 Volume 40 Issue 12 Pages 2105-2109
Several studies reported that the administration of oxaliplatin often induced allergy, but few studies have analyzed the pathogenesis. In this study, we examined the relationship between the incidence of allergy and status of oxaliplatin administration, patient background, laboratory data, or combined drugs. The subjects were 144 patients with colorectal or gastric cancer in whom oxaliplatin administration was started and completed between 2010 and 2016. They were divided into 2 groups: allergy and non-allergy groups. We extracted important factors influencing its appearance using multivariate analysis, and analyzed items of which the influence was suggested, using receiver operating characteristic (ROC) analysis. In 11 patients (7.6%), allergy appeared. The median frequency of appearance was 9 times (range: 5–13), being similar to that previously reported. On multivariate analysis, albumin (Alb) was extracted as an important factor. The cut-off value of Alb for the risk of allergy was 4.1 g/dL. An increase in the number of protein conjugates may have increased the risk of functioning as a hapten. Furthermore, the results suggested that the more frequency of oxaliplatin administration might increase the incidence of allergy, although it was not extracted as an important factor. In addition to young and female patients, as previously indicated, careful follow-up may be necessary for those with an Alb level of ≥4.1 g/dL especially after the 6th course.
Oxaliplatin is a third-generation, platinum complex antitumor agent. Blockage of DNA synthesis through cross-linking with the DNA base may be involved in the action mechanism of this agent, as reported for other platinum complex antitumor agents. Structurally, this agent has the 1,2-diaminocyclohexane group as a carrier ligand, as well as the oxalate group as a leaving group, differing from other platinum complex antitumor agents. It exhibits a potent antitumor activity against colorectal cancer cell strains, and is used as a primary drug for colonic/rectal cancer. Recently, its indication for pancreatic/gastric cancer was approved.1,2) Main adverse reactions include peripheral neuropathy, bone marrow suppression, digestive symptoms, and allergy. According to an international systematic review, the incidences of allergy in oxaliplatin-, cisplatin-, and carboplatin-treated patients were 10 to 18.9, 5 to 20, and 1 to 44%, respectively.3) The percentage in the oxaliplatin group was relatively higher than those in the other groups, possibly because the molecular weight of oxaliplatin is higher than those of the other platinum complex antitumor agents (oxaliplatin: 397.29, cisplatin: 300.05, and carboplatin: 371.25).4) In clinical practice, the regimen is frequently changed due to allergy. However, few studies have examined the detailed mechanism involving laboratory data etc. In this study, we investigated the relationship between the incidence of allergy and status of oxaliplatin administration, patient background, laboratory data, or combined drugs, and analyzed factors involved in the appearance of allergy.
All patients with colorectal or gastric cancer in whom oxaliplatin (ELPLAT®, Yakult Honsha Co., Ltd., Tokyo, Japan) administration was started and completed at Mazda Hospital of Mazda Motor Corporation (Hiroshima, Japan) between 2010 and 2016.
Inclusion CriteriaPatients who received the following registered regimens:
No exclusion criterion was established.
Survey ItemsThe following items were retrospectively investigated using electronic medical records.
Patient background and laboratory data were investigated on the first administration day.
Combined drugs were investigated at the time of appearance of allergy or on the final administration day.
The results were calculated as the mean±standard deviation (S.D.). To compare the frequency of oxaliplatin administration and cumulative dose between the allergy and non-allergy groups, Mann–Whitney’s U-test was used. To compare the patient background, Student’s t-test or Fisher’s direct probability test was conducted. The laboratory data were compared using Student’s t-test or Mann–Whitney’s U-test. For the comparison of combined drugs, Mann–Whitney’s U-test or Fisher’s direct probability test was performed. To extract important factors influencing the appearance of allergy, multivariate analysis (two-value logistic regression analysis) was conducted using the presence or absence of its appearance as an objective variable, and the frequency of oxaliplatin administration and the Alb level (p<0.1 on univariate analysis) as explanatory variables. In addition, we performed receiver operating characteristic (ROC) analysis regarding the Alb level, of which the influence on the appearance of allergy was suggested on multivariate analysis, and calculated a cut-off value for the risk of allergy. For cut-off calculation, the way to choose the closest point to the left top corner of the graph was used. All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modified version of R commander designed to add statistical functions frequently used in biostatistics.5) A p-value of 0.05 was regarded as significant.
Ethical ApprovalThis study was approved by the Medical Ethics Committee of Mazda Hospital of Mazda Motor Corporation.
The subjects were 144 patients. Of these, allergy appeared in 11 (7.6%): Grade 2 allergic reactions in 5 (3.5%) and Grade 3 anaphylaxis in 6 (4.2%).
The median frequency of oxaliplatin administration was 9 times (range: 5–13) in the allergy group and 7 times (range: 1–22) in the non-allergy group; there was significant difference (p=0.049). The median cumulative doses of oxaliplatin were 915 mg (range: 500–2070) in the allergy group and 900 mg (range: 100–2540) in the non-allergy group, showing no significant difference (p=0.609). The incidence of allergy with respect to the cumulative frequency of administration is shown in Fig. 1.
Concerning the patient background, there was no significant difference in any item between the two groups (Table 1).
| Allergy group (n=11) | Non-allergy group (n=133) | p-Value | |
|---|---|---|---|
| Age (years) | 64.5±11.2 | 68.2±9.1 | 0.203*1 |
| Sex: Male/female (persons) | 6/5 | 96/48 | 0.873*2 |
| Males only (%) | 6.3 | 93.7 | — |
| Females only (%) | 10.4 | 89.6 | — |
| Height (cm) | 160.2±8.7 | 161.1±9.3 | 0.768*1 |
| Body weight (kg) | 58.4±17.1 | 57.0±12.5 | 0.723*1 |
| Body surface area (m2) | 1.55±0.23 | 1.55±0.19 | 0.921*1 |
| BMI (kg/m2) | 22.6±5.5 | 21.8±3.7 | 0.536*1 |
| PS (ECOG) | All patients: 0 or 1 | All patients: 0 or 1 | — |
| Allergy predisposition: Present/absent (persons) | 6/5 | 42/91 | 0.113*2 |
| Previous chemotherapy: Present/absent (persons) | 5/6 | 38/95 | 0.199*2 |
| Carcinoma: Colorectal cancer/gastric cancer (persons) | 11/0 | 117/16 | — |
Data are presented as the mean±standard deviation, n, or score. *1 Student’s t-test. *2 Fisher’s exact test. BMI, body mass index; PS, Performance Status.
Concerning the laboratory data, there was a significant difference in the Alb level between the two groups (p=0.011) (Table 2).
| Allergy group (n=11) | Non-allergy group (n=133) | p-Value | |
|---|---|---|---|
| AST (IU/L) | 28.8±15.1 | 26.3±18.6 | 0.585*1 |
| ALT (IU/L) | 39.2±36.1 | 26.1±22.5 | 0.280*1 |
| T-Bil (mg/dL) | 0.53±0.15 | 0.58±0.26 | 0.836*1 |
| CRE (mg/dL) | 0.66±0.16 | 0.78±0.27 | 0.168*2 |
| Alb (g/dL) | 4.2±0.4 | 3.7±0.6 | 0.011*2 |
Data are presented as the mean±standard deviation. *1 Mann–Whitney’s U-test. *2 Student’s t-test. AST, aspartate aminotransferase; ALT, alanine aminotransferase; T-Bil, total bilirubin; CRE, creatinine; Alb, albumin.
The Alb level was examined with respect to the presence or absence of allergy, as shown in Fig. 2.
Concerning combined drugs, there was no significant difference in any item between the two groups (Table 3).
| Allergy group (n=11) | Non-allergy group (n=133) | p-Value | |
|---|---|---|---|
| Molecule-targeting drugs: Present/absent (persons) | 5/6 | 50/83 | 0.416*3 |
| Breakdown | |||
| Cetuximab | 1 | 9 | |
| Trastuzumab | 0 | 1 | |
| Panitumumab | 0 | 3 | |
| Bevacizumab | 4 | 37 | |
| Dose of a steroid (mg)*1 | 300.0±144.2 | 323.6±164.4 | 0.755*4 |
| The influence of an aprepitant was considered*2 | |||
| Dose of a steroid (mg)*1 | 180.0±49.7 | 205.6±70.8 | 0.227*4 |
| The influence of an aprepitant was not considered | |||
| Histamine H1 receptor antagonists: Present/absent (persons) | 1/10 | 34/99 | 0.200*3 |
| Histamine H2 receptor antagonists: Present/absent (persons) | 2/9 | 37/96 | 0.385*3 |
| Aprepitants: Present/absent (persons) | 7/4 | 74/59 | 0.427*3 |
Data are presented as the mean±standard deviation or n. *1 Converted to hydrocortisone. *2 Steroid dose ×2. *3 Fisher’s exact test. *4 Mann–Whitney’s U-test.
Multivariate analysis (two-value logistic regression analysis) was conducted using the presence or absence of allergy appearance as an objective variable, and the frequency of oxaliplatin administration and the Alb level (p<0.1 on univariate analysis) as explanatory variables. The results suggested the influence of Alb on the appearance of allergy (odds ratio: 5.23, 95% confidence interval: 1.32–20.81, p=0.019) (Table 4).
| Odds ratio | 95% confidence interval | p-Value | |
|---|---|---|---|
| Alb | 5.23 | 1.32–20.81 | 0.019 |
| Frequency of oxaliplatin administration | 1.11 | 0.94–1.31 | 0.206 |
Alb, albumin.
ROC analysis regarding Alb, of which the influence on allergy appearance was suggested on multivariate analysis (two-value logistic regression analysis), was performed. The results showed that an Alb level of ≥4.1 g/dL was a risk factor (area under curve (AUC)=0.724, 95% confidence interval: 0.591–0.857) (Fig. 3).
The incidence of allergy was 13.5% in patients with Alb level above 4.1 g/dL, whereas 4.4% in patients with Alb level less than 4.1 g/dL. From subanalysis between the allergy and non-allergy groups with Alb level above 4.1 g /dL, there was no significant difference in any item (data not shown).
Oxaliplatin-induced allergy may be primarily associated with the mechanism of type I allergy.3,6) Urticaria, hot flushes, mucosal edema, or a reduction in the blood pressure occurs within a few minutes after exposure to a causative substance; therefore, type I is termed immediate allergy. This reaction is induced by immunoglobulin E (IgE) antibody. When this antibody adhered onto the surfaces of mast cells or basophils is again exposed to an antigen, inter-IgE-antibody cross-linking occurs, and intracellular granules are released (degranulation). As intracellular granules contain a large amount of inflammatory mediators, such as histamine, serotonin, and heparin, degranulation induces rapid vasodilation or enhances the vascular permeability, leading to edema or a reduction in the blood pressure through the extravascular leakage of plasma components.7)
In this survey, the appearance of immediate allergy was noted in 7.6% of the patients. We compared the incidence of allergy with that in previous studies. According to a systematic review, it ranged from 10 to 18.9%,3) and Kim et al. indicated that it was 11.7%.8) Honda et al. reported that the incidence was 17.9%9); the percentage of our study was slightly lower than other reports. Furthermore, the incidence of serious allergy was 4.2%, but it was 1.6, 1.6, and 5.3%, respectively, according to the systematic review, Kim et al., and Honda et al.3,8,9); in Japan, the incidence was slightly higher than in other countries. The dosage and administration were similar between Japan and other countries, and the possibility of race difference-related allergy must be reviewed in the future.
At the time of appearance, the median frequency of oxaliplatin administration was 9 times (range: 5–13). It was ≥6 times according to the systematic review,3) 7 times (range: 1–11) according to Kim et al.,8) and 9 times (range: 2–23) according to Honda et al.9); the results were similar. Therefore, the 6th course or later must be administered, considering the appearance of allergy.
Concerning the patient background, previous studies reported that risk factors included a young age and female gender.3,8) In this survey, the mean age in the allergy group was slightly younger than in the non-allergy group, and the rate of females was slightly higher, although there were no significant differences.
Concerning the laboratory data, there was a significant difference in the Alb level. Antigen-presenting cells present a hapten (an immunogenicity-free antigen with reactogenicity, which acquires immunogenicity by binding to a macromolecular carrier protein. In the case of drug allergy, a drug functions as a hapten), that is, a drug or its metabolites plus proteins or peptides, to naïve T cells (T cells without a history of antigen exposure). The antigen-specific T cells proliferate, infiltrating the skin, releasing cytokines, chemokines, and proinflammatory mediators, contributing to drug rash.4,10–14) Oxaliplatin may also act as a hapten, binding to macromolecular carrier proteins, such as albumin and γ-globulin, at a rate of ≥90%1) and acquiring immunogenicity. In this study, the Alb level in the allergy group was significantly higher than in the non-allergy group. This may have been because an increase in the number of protein conjugates increased the risk of functioning as a hapten.
Concerning combined drugs, there was no significant difference in any item. With respect to aprepitants, which are reported to inhibit the selective binding of Substance P to neurokinin-1 receptors and suppress paclitaxel-induced hypersensitivity reactions,15–18) there was no difference related to the presence or absence of medication. This may have been associated with differences in the pathogenesis of allergy.
Multivariate analysis (two-value logistic regression analysis) was conducted using the presence or absence of allergy appearance as an objective variable, and the frequency of oxaliplatin administration and the Alb level (p<0.1 on univariate analysis) as explanatory variables. The results suggested the influence of Alb on allergy appearance. In addition, ROC analysis regarding Alb, of which the influence on allergy appearance was suggested on multivariate analysis (two-value logistic regression analysis), was performed. The results showed that an Alb level of ≥4.1 g/dL was a risk factor.
This was a clinical, retrospective survey; we cannot rule out the possibility that the results may have been influenced by various biases, but it was newly suggested that an Alb level of ≥4.1 g/dL is a risk factor. Considering previously reported risk factors, such as a young age and female gender, careful follow-up may be necessary especially after the 6th course.
The authors declare no conflict of interest.
