We retrospectively analyzed the records of 245 colorectal cancer patients (1,690 treatment cycles) who 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 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)
|
0.574
|
1
|
133 (87.5)
|
79 (84.9)
|
|
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
|
|
|
|
mFOLFLOX
|
15 (9.9)
|
16 (17.2)
|
0.059
|
CapeOx
|
104 (68.4)
|
66 (71.0)
|
|
FLOX
|
33 (11.8)
|
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]
|
0.844b
|
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, a Fisher's Exact Test |
mFOLFLOX: oxaliplatin plus leucovorin and 5-Fluorouracil every 2 weeks |
XELOX: 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 a history of drug hypersensitivity between the patients without HSR (control group) and with HSR (case group). Compared with women, men had a higher susceptibility to HSR (p=0.015). Those patients who had been exposed to platinum compound prior to this episode of treatment also had higher HSR reports (p=0.009). Baseline biochemical examination of blood showed that the percentage of lymphocytes, eosinophiles 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 first and second infusion course, 10 (43.48%) had been exposed to platinum agents prior to 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 of blood pressure. (Table 2) Eleven patients were diagnosed 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)
|
Peripheral neuropathy
|
53 (21.63)
|
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 platinum exposure
|
Metastasis
|
Regimen
|
Purpose
|
Dose per BSA (mg/m2)
|
Cycle number 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-evaluation
|
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 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 was 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. rechallenges (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. SymbicortTM (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]
|
A=Adjuvant, P=Palliative, CMT=chemotherapy |
Risk factors for hypersensitivity reaction
To investigate the potential risk factors for the development of oxaliplatin HSR, we initiated 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. Though 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 analysis
|
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 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)] + [0.818x (if prior platinum exposure)] + [0.003x(number of eosinophil count)] - [0.002x(number of monocyte count)] - [1.111x(serum albumin)]