Abstract
Background:
Oxaliplatin is a third-generation platinum compound that has efficacy against colorectal cancer. Hypersensitivity reactions during oxaliplatin infusion are a key problem during its use, with the varying incidences and deficiencies of clearly identified risk factors.
Objective:
To determine the incidence, severity and risk factors of oxaliplatin-related hypersensitivity reaction (HSR).
Method:
This retrospective study investigated 245 colorectal cancer patients (1,690 treatment cycles) receiving care at King Chulalongkorn Memorial Hospital, Thai Red Cross society between January 1, 2015 and December 31, 2019. The patients’ demographic data, laboratory data and clinical features suggesting hypersensitivity reactions to oxaliplatin were reviewed. The Fisher’s Exact test and unpaired t-test were used to determine the differences among patients with and without oxaliplatin HSR. The potential risk factors for oxaliplatin HSR were analyzed for statistical significance by logistic regression.
Results:
A total of 245 colorectal cancer patients (1,690 treatment cycles) were included in this study. The incidence of oxaliplatin HSR was 37.96%, according to the US National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (NTCAE) version 5.0, grade 1, grade 2 and higher grades were 27.35% (67 patients), 6.53% (16 patients) and 4.08% (10 patients), respectively. The proportion of male patients and patients with a history of prior exposure to platinum-based chemotherapy were statistically higher in the HSR group. The eosinophil count and serum creatinine level were also significantly greater in the HSR group. On the contrary, the total lymphocyte count and serum albumin level were significantly lower in the HSR group. The multivariate logistic regression found 5 risk factors with a significant difference. Male gender, prior exposure to platinum-based chemotherapy and elevated eosinophil count were associated with increased risk of oxaliplatin HSR, whereas elevated monocyte count and elevated serum albumin were protective factors for the development of oxaliplatin HSR.
Conclusion:
Colorectal cancer patients treated with an oxaliplatin-based regimen with male gender, prior exposure to platinum-based chemotherapy and elevated eosinophil count have a greater risk of oxaliplatin related hypersensitivity reactions.
Keywords: Oxaliplatin, Hypersensitivity reactions, Colorectal cancer, Risk factors
INTRODUCTION
Colorectal cancer (CRC) is the fourth most common cancer and the second leading cause of death due to cancer globally.1,2 In Thailand, CRC accounts for 11% of cancer burden, which is the only malignancy with an increased incidence in both sexes.3 CRC treatment is presently a public health priority and comprised of non-pharmacotherapeutic modalities and pharmacotherapy. 5-fluorouracil (5-FU)/leucovorin (LV) or capecitabine are the backbones of the chemotherapeutic regimen, combined with either oxaliplatin (a DNA cross-linker) or irinotecan (a topoisomerase-1 inhibitor). Oxaliplatin-based regimens, such as FOLFOX or CAPEOX, are used more often than irinotecan-based regimen, because of higher efficacy. Consequently, oxaliplatin plus 5-FU/LV or capecitabine, are the mainstreams for both adjuvant and advanced treatments of CRC.4,5
Oxaliplatin is a third-generation platinum compound with a 1,2-diaminocyclohexane carrier ligand, has been approved both for treatment of metastatic colorectal cancer and adjuvant treatment in combination with 5-FU and LV or capecitabine.6 The National Comprehensive Cancer Network (NCCN) guidelines recommended the FOLFOX or CAPEOX as standard regimens for adjuvant chemotherapy for stage II CRC with high-risk factors and stage III CRC as well as the first-line regimen for metastatic CRC.7,8 The modified FOLFOX regimen, comprises of oxaliplatin 85 mg/m2 concurrent with LV, 200-400 mg/m2 on day 1, followed by a bolus 5-FU, 400 mg/m2, on day 1 and a continuous 5-FU, 1,200 mg/m2/day, on day 1 and 2 repeated every 2 weeks for 12 cycles. The CAPEOX regimen consists of oxaliplatin, 130 mg/m2 on day 1 and oral capecitabine 1,000 mg/m2 twice daily on days 1 to 14 of a 3-week cycle for 8 cycles.9
The common adverse reactions of oxaliplatin include nausea, vomiting, diarrhea, and peripheral neuropathy. These adverse reactions can be managed by dosage modification or pre-medication. The serious adverse reactions involve hematologic toxicities, presented as neutropenia and thrombocytopenia. Hypersensitivity reaction (HSR) is another serious adverse effect that should be concerned.10,11 HSR to oxaliplatin has been less frequently described than cisplatin or carboplatin. At the first use, the incidence of HSR to oxaliplatin was very rare, but after the expanded use of oxaliplatin in clinical practice, we are now encountering a significantly increased incidence of oxaliplatin-HSR. Recent reports have shown that the rate of HSR to oxaliplatin has varied from 8.9% to 23.8%.12-14 HSR to oxaliplatin should be of concern, due to its unpredictability, it is potentially life-threatening requiring the subsequent treatment withdrawal. Yu et al 2021, reported that 85.6% of cancer patients with oxaliplatin-HSR had to interrupt the oxaliplatin course and needed corresponding treatment.15 Identifying patients with risk of oxaliplatin-HSR is a key clinical issue and several studies have shown supporting risk factors, with various results.14,16-19 Kim BH et al., 2009 retrospectively analyzed patients receiving oxaliplatin and HSR was associated with younger mean age, female gender and with use of oxaliplatin as salvage therapy.17 Seki K et al., 2011 reported 5 risk factors associated with oxaliplatin-HSR in CRC patients including female, preexisting allergies, lower level of lactate dehydrogenase (LDH), higher neutrophil count and lower monocyte count.18 Kim MY et al., 2012 reviewed all patients treated with oxaliplatin and HSR correlated with lower dexamethasone doses.14 Parel M et al., 2014 identified that developing oxaliplatin-HSR increased with women, younger patients and patients with prior exposure to platinum salts.19 The aforementioned studies were conducted among patients in the United States, France, South Korea, Japan and China which could be different from Thai patients. In this retrospective study, we explored the incidence, severity and risk factors of oxaliplatin-HSR among Thai patients with CRC.
METHOD
We conducted a retrospective review of the medical records of colorectal cancer patients treated with oxaliplatin-based regimen at King Chulalongkorn Memorial Hospital, Thai Red Cross society, Thailand between January 1, 2015, and December 31, 2019. This study was approved by the Institutional Review Board (IRB), Faculty of Medicine, Chulalongkorn University (IRB no. 323/61).
All patients received intravenous dexamethasone 8 mg and ondansetron 8 mg as premedication before oxaliplatin infusion. Oxaliplatin-HSR was assessed and classified according to the National Cancer Institute Common Criteria (NCI-CTCAE v5.0)20 and was noted by attending healthcare staff in the medical records.
Data collection
1) Patient characteristics: gender, age, body surface area (BSA), Eastern Cooperative Oncology Group (ECOG) performance status; scale describing a patient’s level of functioning in terms of their ability to care for themselves, daily activity and physical ability21, medical conditions and preexisting allergies (allergy to specific food or drug). 2) Cancer and chemotherapy characteristics: type of cancer, purpose of treatment, treatment regimen, oxaliplatin dose administration, prior exposure to platinum-based chemotherapy, the number of cycles administered when the episode occurred and the severity of HSR. 3) Baseline laboratory data were obtained for 1 month before the day of administration of oxaliplatin regimen: serum creatinine, serum glutamic-oxaloacetic transaminase (SGOT), serum glutamate-pyruvate transaminase (SGPT), alkaline phosphatase (ALP), serum albumin, white blood cell (WBC) count, neutrophil count, lymphocyte count, monocyte count and eosinophil count.
In addition, the management, the response to treatment, the mode of prevention used during rechallenging and the final decision (oxaliplatin continuation or withdrawal) were reviewed.
Data analysis
Statistical analysis was performed using the SPSS software, version 22 (IBM Corp., Armonk, NY, USA). After collecting the data, we imputed the missing data by using multiple regression. Quantitative data are reported as means and standard deviation and qualitative data are shown as numbers and percentage. Incidence was defined as the number of cases divided by the total number of patients included in the study. The correlations between HSR to oxaliplatin and several background factors were statistically analyzed using Fisher’s exact test or the unpaired t-test. In statistical testing, two-sided p-values ≤ 0.05 were considered statistically significant.
The risk factors examined included gender, age, BSA, ECOG performance status, preexisting allergies and pre-exposure to platinum chemotherapy. The results from laboratory test data were also analyzed. To determine risk factors potentially associated with HSR to oxaliplatin, those factors were collected and subjected to univariate and multivariate logistic regression. All variables with p-values < 0.2 were included in the initial multivariate model. Multivariate analysis with backward stepwise elimination was then conducted to develop the final model. The goodness of fit for each stepwise model was compared with Hosmer and Lemeshow test. A p-value of < 0.05 was considered significant.
RESULTS
Patient characteristics
We retrospectively analyzed the records of 245 colorectal cancer patients (1,690 treatment cycles) who were treated with oxaliplatin-based regimens. The median age was 61 years (range 33-88 years) and 142 (57.96%) were male. Approximately 70% of patients had received capecitabine plus oxaliplatin regimen (CAPEOX). The background characteristics of colorectal cancer patients who had a positive and negative experience of oxaliplatin-HSR and the baseline laboratory data were listed in Table 1.
Table 1.
Patient characteristics (n=245)
| Parameter | Number of patients (%) | p-value | |
|---|---|---|---|
| Patient without HSR (n=152) [Max,Min] | Patient with HSR (n=93) [Max,Min] | ||
| Age (years), mean ± SD | 59.34±11.38 [81,33] | 59.96±11.19 [88,40] | 0.677 |
| Gender: Male/Female | 79 (52.0)/73 (48.0) | 63 (67.7)/30 (32.3) | 0.015* |
| Body surface area (m2), mean ± SD | 1.62±0.19 [2.23,1.12] | 1.64±0.15 [2.01,1.27] | 0.370 |
| ECOG Performance Status | |||
| 0 | 1 (0.7) | 0 (0.00) | |
| 1 | 133 (87.5) | 79 (84.9) | 0.574 |
| 2 | 18 (11.8) | 14 (15.1) | |
| Metastasis, yes | 88 (57.9) | 46 (49.5) | 0.198 |
| Prior exposure to platinum-based chemotherapy, yes | 18 (11.8) | 23 (24.7) | 0.009* |
| History of drug hypersensitivity, yes | 13 (5.3) | 12 (4.9) | 0.275 |
| Underlying medical condition, yes | 97 (63.8) | 55 (59.1) | 0.499 |
| Regimen | |||
| CAPEOX | 104 (68.4) | 66 (71.0) | |
| mFOLFLOX | 15 (9.9) | 16 (17.2) | 0.059 |
| FLOX | 33 (21.7) | 11 (11.8) | |
| Purpose | |||
| Adjuvant | 81 (53.3) | 70 (75.3) | 0.001* |
| Palliative | 71 (46.7) | 23 (24.7) | |
| Dose (mg), mean ± SD | 177.36±45.78 [250,65] | 183.06±37.51 [250,100] | 0.290 |
| Dose per body surface area (mg/m2), mean ± SD | 108.71±23.70 [135.80, 43.62] | 111.58±21.55 [142.86,55.87] | 0.342 |
| Cumulative dose (mg), mean ± SD | 1160.53±471.58 [2040,125] | 1234.11±465.85 [2400,180] | 0.235 |
| Total infusion course, median | 8 [12,1] | 7 [12,1] | 0.844a |
| WBC count (x103/μL) | 6.95±2.26 [14.74,2.19] | 6.78±2.05 [14.07,3.99] | 0.329 |
| Neutrophil count (cells/mm3) | 4468.09±1922.92 [12087,1473] | 4414.39±1764.801 [11017,1828] | 0.827 |
| Total lymphocyte count (cell/mm3) | 1690.83±914.56 [6222,131] | 1459.30±639.54 [3185,356] | 0.033* |
| Monocyte count (cell/mm3) | 479.01±192.56 [995.80,37.98] | 444.97±210.39 [1210.02,24.00] | 0.196 |
| Eosinophil count (cell/mm3) | 142.41±134.24 [716,0] | 189.45±170.32 [961,0] | 0.017* |
| Serum albumin (g/dL), n=171 | 3.76±0.46 [4.5,2] n=98 | 3.59±0.54 [5,2] n=73 | 0.024* |
| Alkaline phosphatase (U/L) | 90.89±94.71[869,20] | 96.91±98.82 [573,21] | 0.635 |
| Serum creatinine (mg/dL) | 0.78±0.19 [1.3,0.3] | 0.84±0.28 [2.2,0.5] | 0.073 |
| - more than 1 mg/dL | 14 (9.2) | 20 (21.5) | 0.007* |
| eGFR (mL/min) | 83.84±27.22 [199.84,26.22] | 83.23±26.29 [137.67,15.86] | 0.863 |
P < 0:05,
Mann-Whitney's U-test
mFOLFLOX: Oxaliplatin plus leucovorin and 5-Fluorouracil every 2 weeks
CAPEOX: Intravenous oxaliplatin 130 mg/m2 (day 1) followed by oral capecitabine 1,000 mg/m2 twice daily (day 1, evening, to day 15, morning)
WBC white blood cell
FLOX: 5-Fluorouracil plus oxaliplatin on weeks 1,3,5 of 8-week cycle
SGOT: Serum glutamic-oxaloacetic transaminase
SGPT: Serum glutamate-pyruvate transaminase
eGFR: estimated glomerular filtration rate
There were no statistical differences of age, body surface area, dosage regimen, performance status, total infusion course, and history of drug hypersensitivity between the patients without HSR (control group) and with HSR (case group). Compared with women, men had relatively higher susceptibility to HSR (p=0.015). Those patients who had been exposed to platinum compound before this episode of treatment also had higher HSR reports (p=0.009). Baseline biochemical examination of blood showed that the percentage of lymphocytes, eosinophils and serum albumin were statistically different between the 2 groups (p=0.044, 0.012, 0.024 respectively).
Incidences of hypersensitivity reaction
During the 5-year follow-up, 93 patients experienced oxaliplatin-HSR. According to NCI-CTCAE v.5, the incidence rate of grade 1, grade 2 and higher grade was 27.3% (67 patients), 6.5% (16 patients) and 4.1% (10 patients), respectively. (Table 2) Oxaliplatin hypersensitivity appeared on a median of 3 infusions (1-11). In addition, out of 23 patients (9.39%) who developed oxaliplatin-HSR at the first and second infusion course, 10 (43.48%) had been exposed to platinum agents before this episode of treatment. The most common HSR were mild cutaneous reactions such as flushing, urticaria, itching and small area erythema, largely on palms and soles. Some patients presented more severe reactions with facial swelling, dyspnea, wheezing, stomach cramp, diarrhea, or changes in blood pressure. (Table 2) Eleven patients were diagnosed with anaphylaxis, with acute and severe symptoms during the infusion or started within 30 minutes after complete infusion. Ten of these were grade 3 HSR, in which the oxaliplatin infusion was immediately discontinued when the reaction occurred and was promptly handled before being admitted into the hospital. (Table 3)
Table 2.
Severity and manifestations of oxaliplatin hypersensitivity reactions (n=245)
| Number of patients (%) | |
|---|---|
| Incidence of hypersensitivity | 93 (37.96) |
| Severity | |
| Grade 1 | 67 (27.35) |
| Grade 2 | 16 (6.53) |
| Grade 3/4 | 10 (4.08) |
| Symptom | |
| Cutaneous reactions | 58 (23.67) |
| Anaphylaxis | 11 (4.49) |
| Digestive symptoms | 20 (8.16) |
| Respiratory symptoms | 17 (6.94) |
| Blood pressure rising | 6 (2.45) |
| Fever/Chill | 4 (1.63)/6 (2.45) |
| Palpitation | 3 (1.22) |
| Blood pressure lowering | 2 (0.82) |
| Cycle number at event, median (range) | 3 (1-11) |
| Grade 2, median (range) | 4 (1-11) |
| Grade 3, median (range) | 2.5 (1-6) |
Table 3.
Characteristics of the ten patients with grade 3/4 oxaliplatin hypersensitivity
| No., Gender, Age (years) | Prior plt exp | Metastasis | Regimen | Purpose | Dose/BSA (mg/m2) | Cycle No. at event | Onset of HSR (minutes) | Total cycle | Treatment | Management |
|---|---|---|---|---|---|---|---|---|---|---|
| 1,F,59 | N | N | CAPEOX | A | 130 | 5 | 50 | 5 | 1. CPM 10 mg, Dexamethasone 5 mg IV STAT 2. Hold 30 minutes then slow infusion about 6 hours |
Discontinue and adjust to single capecitabine then re-evaluate |
| 2,M,59 | N | N | CAPEOX | A | 130 | 2 | 90 | 6 | 1. Discontinue 2. Hyoscine-N-butyl bromide 20 mg IV STAT and hydration |
1. Add loperamide 2 mg Sig. 2 caps on CMT day 2. Add CPM 10 mg IV pre CMT 3. Rechallenge with prolonged infusion time (4 hours), finally complete total 6 cycles |
| 3,F,60 | Y | N | mFOLFLOX | A | 85 | 2 | 20 | 12 | 1. Hold and reduce rate of administration to 80 mL/hr 2. CPM 10 mg, Dexamethasone 5 mg IV STAT 3. Adrenaline 0.3 mg IM |
12 step desensitization protocol, finally complete total 12 cycles |
| 4,F,62 | Y | Y | FLOX | P | 80 | 2 | 120 | 4 | 1. Adrenaline 1 mg IM and hydration | 1. 12 step desensitization protocol with mild HSR through desensitization. 2. Patient requested to discontinue after the 4th cycle |
| 5,M,47 | N | N | mFOLFLOX | A | 85 | 3 | 110 | 8 | 1. Discontinue 2. Dexamethasone 10 mg IV STAT 3. Adrenaline 0.5 mg IM |
1. 12 step desensitization protocol, but grade-2 HSR through to the 8th cycle 2. Discontinue after the 8th cycle |
| 6,M,45 | Y | N | CAPEOX | A | 100 | 2 | 15 | 3 | 1. Hold 2. Adrenaline 0.3 mcg IM and hydration 3. Admit and rechallenge oxaliplatin 20-40 mL/hr |
1. Rechallenge with prolonged infusion time (4 hours), grade 2 HSR occurred so discontinue. 2. Skin test: Positive |
| 7,M,47 | Y | N | FLOX | P | 85 | 1 | 90 | 6 | 1. Hold and oxygen therapy 2. Adrenaline 0.5 mg IM and Dexamethasone 10 mg IV 3. Admit and then slow infusion about 4 hours |
1. Skin test: Negative 2. rechallenge (2nd cycle) with prolonged infusion time (6 hours), but mild HSR. 2. 12 step desensitization protocol (3rd -6th cycle) |
| 8,M,56 | N | N | mFOLFLOX | A | 80 | 6 | 80 | 6 | 1. Hold 2. Symbicort™ (160/4.5) 4 puffs and oxygen therapy 3. CPM 10 mg IV 4. Continue infusion rate 80 mL/hr |
Discontinue according to therapeutic plan |
| 9,M,44 | N | N | CAPEOX | A | 90 | 6 | 120 | 6 | 1. Hyoscine-N-butyl bromide 20 mg IV and CPM 10 mg IV STAT | Discontinue according to therapeutic plan |
| 10,F,73 | Y | Y | CAPEOX | P | 120 | 3 | 120 | 3 | 1. Loperamide 2 mg 2 capsules STAT 2. Hydration |
Discontinue [Hand foot syndrome grade 3] |
No.=Number
Prior plt exp= Prior platinum exposure
Purpose: A=Adjuvant, P=Palliative
CMT=Chemotherapy
HSR= Hypersensitivity reaction
mFOLFLOX: Oxaliplatin plus leucovorin and 5-Fluorouracil every 2 weeks
CAPEOX: Intravenous oxaliplatin 130 mg/m2 (day 1) followed by oral capecitabine 1,000 mg/m2 twice daily (day 1, evening to day 15, morning)
Risk factors for hypersensitivity reaction
To investigate the potential risk factors for the development of oxaliplatin HSR, we applied a logistic regression model, in which the following factors were included: (1) age, (2) gender, (3) metastasis, (4) prior platinum exposure, (5) history of drug hypersensitivity, (6) neutrophil count, (7) lymphocyte count, (8) monocyte count, (9) eosinophil count, (10) serum albumin, (11) serum creatinine, (12) oxaliplatin infusion number and (13) total dose of oxaliplatin. Through the univariate analysis, in total 8 factors had p-values < 0.2 which met the criteria for inclusion in multivariate analysis (Table 4).
Table 4.
Univariate analysis and multivariate analysis for candidate risk factors for oxaliplatin hypersensitivity [N=245]
| Univariate analysi s | Multivariate analysis | |||||||
|---|---|---|---|---|---|---|---|---|
| Factors | B | Adjusted OR | 95%CI | p-value | B | Adjusted OR | 95%CI | p-value |
| Age | 0.005 | 1.005 | 0.982-1.028 | 0.675 | ||||
| Gender, male | 0.663 | 1.941 | 1.132-3.326 | 0.016* | 0.966 | 2.628 | 1.450-4.763 | 0.001 |
| Metastasis, yes | -0.034 | 0.712 | 0.424-1.196 | 0.199 | ||||
| Prior platinum exposure, yes | 0.894 | 2.446 | 1.238-4.834 | 0.010* | 0.818 | 2.265 | 1.079-4.755 | 0.031 |
| History of drug hypersensitivity, yes | 0.460 | 1.584 | 0.69-3.637 | 0.278 | ||||
| Neutrophil count (cell/mm3) | 0.0002 | 0.99998 | 0.9998-1.0002 | 0.826 | ||||
| Total lymphocyte count (cell/mm3) | 0.0004 | 0.9996 | 0.9992-0.9999 | 0.037* | ||||
| Monocyte count (cell/mm3) | -0.001 | 0.999 | 0.998-1.000 | 0.197 | -0.002 | 0.998 | 0.996-0.999 | 0.007 |
| Eosinophil count (cell/mm3) | 0.002 | 1.002 | 1.000-1.004 | 0.020* | 0.003 | 1.003 | 1.001-1.005 | 0.004 |
| Serum albumin (g/dL) | -0.787 | 0.455 | 0.258-0.804 | 0.007* | -1.111 | 0.329 | 0.170-0.638 | 0.001 |
| Serum creatinine (mg/dL) | 1.128 | 3.090 | 0.984-9.707 | 0.053 | ||||
| Oxaliplatin infusion number (times) | 0.028 | 1.028 | 0.929-1.138 | 0.589 | ||||
| Total dose of oxaliplatin (mg) | 0.0003 | 1.000 | 1.000-1.001 | 0.234 | ||||
| Constant | 3.419 | |||||||
p < 0.05
After the backward stepwise elimination method, 5 final factors were selected: gender, prior platinum exposure, eosinophil count, monocyte count and serum albumin. The odds ratio (95% CI) from the multivariate model was presented in Table 4. We established the incidence of hypersensitivity in colorectal cancer patients treated with this oxaliplatin base regimen(Y) model:
Y=3.419 + [0.966 x (Gender; if male =1)] + [0.818 x (if prior platinum exposure)] + [0.003x(number of eosinophil count in cells/mm3)] - [0.002x(number of monocyte count in cells/mm3)] - [1.111x(serum albumin in g/dL)].
DISCUSSION
Hypersensitivity reactions to oxaliplatin result in the withdrawal of the chemotherapy or reducing the number of therapeutic options. The incidence of oxaliplatin HSR is growing as a consequence of the increasing use of oxaliplatin in colorectal cancer. The incidence of oxaliplatin HSR in this study was 37.96%, relatively higher than the rates described in previous studies (8.9% to 23.8%),12,14,17,22,23 suggesting racial effects and dosage effects. The MOSAIC trial, a large, randomized phase 3 trial in Western countries, showed 10.3% of 1,100 patients who received 5-fluorouracil with oxaliplatin experienced HSR.23 The report from Japanese patients indicated that 22.9% of 108 patients experienced hypersensitivity.18 Additionally, the dose of oxaliplatin in the MOSAIC trial was 85 mg per square meter or was reduced to 75 mg per square meter in the event of persistent neuropathy,23 but the average dose of oxaliplatin in this study was 110 mg per square meter. Interestingly, grade 3/4 HSR in this study was similar to the previous study.18,23 Ten patients experienced grade 3/4 HSR to oxaliplatin and 6 patients were reintroduced to oxaliplatin. The reintroduction of oxaliplatin was done after skin testing for oxaliplatin sensitivity or using a 12-step desensitization protocol, developed by the Dana–Farber Cancer Institute and the Brigham and Women’s Hospital.24
The identification of the risk of developing HSR is an important issue for the prevention and related management of serious events. The risk factors to platinum drugs related to HSR, especially carboplatin and cisplatin were examined. Only a few studies were focused to identify potential risk factors for oxaliplatin-related HSR.25 This study emphasized the risk factors to recognize patients at risk of oxaliplatin-related HSR. Logistic regression analysis found five significant factors, three risk factors (male, prior platinum exposure, eosinophil count) and two protective factors (monocyte count, serum albumin).
Okayama et al., reported that male patients and eosinophil count in peripheral blood were independent variables for oxaliplatin-related HSR,26 which were similar to our finding. Eosinophil, one of the immunologic cells, absolutely characterizes drug HSR, especially drug eruptions, consequently in patients with high eosinophil counts, this may be a component in mechanisms of HSR to oxaliplatin.26,27 This is contrary to Parel et al., Seki et al. and Kim et al., studies which suggested that females were at higher risk of oxaliplatin-related HSR,17-19 explained by a possible role of hormonal influences. Several studies have also reported no correlation between gender and HSR.12,28 Our study demonstrated that prior platinum exposure was the independent risk factor that was distinguished from previous studies.
On the other hand, we found that lower monocyte count and serum albumin was significantly associated with the incidence of oxaliplatin-related HSR. Seki et al., also suggested that female, preexisting allergies, lower LDH level, higher neutrophil count and lower monocyte count were associated with the incidence of HSR.18 Serum albumin is commonly utilized as a marker of nutritional status. Malnutrition degrades both the innate and adaptive immune system.29 Low serum albumin level increases vascular permeability and increases interstitial volume, which potentiates immediate HSR.30 However, Nishihara et al., reported that serum albumin level above 4.1 g/dL was the potential risk associated with the incidence of oxaliplatin-related HSR. Oxaliplatin may also act as a hapten: a small molecule which, when combined with a larger carrier such as a protein can elicit the production of antibodies that bind specifically to it, binding to macromolecular carrier proteins, such as albumin.31 A possible reason for the variation of risk factors was the ethnic differences between the participants in this study. Finally, we found that treatment regimen and oxaliplatin dose were not associated with an increased risk of oxaliplatin-related HSR.
Strength and limitations
This retrospective study was conducted to clarify the risk factors for oxaliplatin-related HSR in Southeast Asia and demonstrated the management of severe oxaliplatin-related HSR in the real situation. Limitations of this study include its retrospective design and incomplete clinical data. Some medical records were insufficient, and hypersensitivity symptoms were not actively followed.
Suggestion
Further prospective studies are needed to refine this oxaliplatin-related hypersensitivity prediction model to be more precise and develop the final model as a guide to prevent oxaliplatin-related HSR. Finally, the caregiver team’s vigilance should be improved with males, prior platinum exposure, eosinophil count, monocyte count and serum albumin.
CONCLUSION
Oxaliplatin-related hypersensitivity is a significant potential adverse reaction. The incidence was approximately 38%, with grade 3/4 events in 4% of patients. In this study, males, prior platinum exposure, eosinophil count, monocyte count and serum albumin were the independent risk factors that were associated with the incidence of oxaliplatin-related hypersensitivity.
ACKNOWLEDGEMENT
We would like to acknowledge Stephen Pinder, a native speaking medical English specialist, for conducting a comprehensive English language review of our manuscript.
Contributor Information
Sirinoot Palapinyo, Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, College of Pharmacotherapy of Thailand, Thailand. Sirinoot.p@pharm.chula.ac.th.
Jettanong Klaewsongkram, Division of Allergy and Clinical Immunology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand. Jettanong.K@chula.ac.th.
Virote Sriuranpong, Division of Allergy and Clinical Immunology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand. Virote.S@chula.ac.th.
Nutthada Areepium, Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand. Nutthada.A@pharm.chula.ac.th.
CONFLICTS OF INTEREST/COMPETING INTERESTS
The authors declare that there have no conflicts of interest.
FUNDING
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
AUTHORS’ CONTRIBUTIONS
All authors contributed to the study conception and design. Material preparation and data collection were performed by Sirinoot Palapinyo. The data analysis was performed by Sirinoot Palapinyo and Nutthada Areepium. The first draft of the manuscript was written by Sirinoot Palapinyo and all authors commented and edited previous versions of the manuscript. All authors read and approved the final manuscript. The content has not been published or submitted for publication elsewhere.
ETHICS APPROVAL
This study was approved by the Institutional Review Board (IRB), Faculty of Medicine, Chulalongkorn University (IRB no. 323/61).
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