Introduction
Oxaliplatin is a
third-generation platinum analog that is mainly used for the treatment of
advanced colorectal cancer, gastric, pancreatic, esophageal, and ovarian
cancers both in the adjuvant and metastatic settings (Devanabanda &
Kasi, 2021). Although peripheral
neuropathy is a major adverse drug reaction in patients receiving oxaliplatin,
mild to moderate vascular pain originating around the injection site during
peripheral intravenous administration of oxaliplatin is also a significant
problem and it develops in 41.2 % in patients who had no risk factor, 52.0 % in
those who had one risk factor and 79.6% in those who had two or more risk
factors (Suga et al., 2018). It lasts during the infusion and less than 1 hour after completion or
interruption (Petrelli et al.,
2015).
The development of vascular
pain and phlebitis following intravenous infusion of antineoplastic agents
subsequently increases the risk of discontinuation of chemotherapy (Nagao et al., 2017). Several methods for preventing or relieving oxaliplatin-induced
vascular pain have been reported in clinical studies. Co-infusion of
dexamethasone (Hata et al., 2015;
Matsuyama et al., 2011; Yoshida et al., 2012), pre-warming the peripheral blood vessels (Miyajima et al.,
2013), premedication with oxycodone,
and changing the dose rate (Nagao et al., 2017) have all been investigated as ways of reducing oxaliplatin-induced
vascular pain. Vascular pain has usually been evaluated by subjective methods,
such as questionnaires and visual analog scale (VAS). The VAS is the most
widely used tool for evaluating pain intensity. Patients were asked to indicate
a point along a 100 mm scale bar depending on the strength of their pain, with
'no pain at all (0) at the left end of the scale and the worst pain (100) at
the right end scale bar. The VAS score is considered to be a good indicator of
subjective pain (Atisook et al., 2021). Patients having oxaliplatin-related vascular pain due to peripheral
administration have a seriously impaired quality of life. Unfortunately, no
drugs have yet been proven effective in alleviating peripheral neuropathy and
vascular pain (Suwa et al., 2019).
Better information on the
variability and frequency of adverse events and their impact on treatment will
enable clinicians to establish strategies that preserve chemotherapy treatment
without unduly incurring the development of vascular pain. The primary objective
of this study was to identify the percentage of oxaliplatin-induced vascular
pain during administration in Iraqi patients. The secondary objective was to
identify the risk factors for vascular pain.
Material and methods
Study design and participants
This is a cross-sectional
observational study carried out at the Al-Andalus private hospital for cancer
patients, Baghdad, Iraq between the period of October 2020 and April 2021. The
study included 101 patients, diagnosed with one of the following cancers:
colon, pancreatic, stomach cancer, and rectal, between the ages of 18 and 80
years, and receiving oxaliplatin peripheral
venous infusion.
Chemotherapy
The following chemotherapy
protocols were administered to the patients:
(A) XELOX protocol (Oxaliplatin +
Capecitabine). Day 1: oxaliplatin 130 mg/m2 IV over 2
hours. Days 1Ð15: Capecitabine 1,000 mg/m2 orally twice
daily. Repeat cycle every 3 weeks.
(B) FLOT protocol (Fluorouracil +
Leucovorin + Oxaliplatin + Docetaxel). Day 1: Docetaxel 50 mg/m2 IV
over 1 hour, oxaliplatin 85 mg/m2 IV over 2 hours, with
Leucovorin 200 mg/m2 IV over 2 hours, followed by Fluorouracil 2600 mg/m2 IV
continuous infusion over 24 hours. Repeat cycle every 2 weeks for 4 cycles
preoperatively and 4 cycles postoperatively for a total of 8 cycles.
(C) FOLFOX protocol (Fluorouracil +
Oxaliplatin + Leucovorin). Day 1: oxaliplatin 85 mg/m2 IV
over 2 hours, with Leucovorin 200 mg/m2 IV over 2
hours, followed by Fluorouracil 2,600 mg/m2 IV continuous
infusion over 24 hours. Repeat cycle every 2 weeks for a total of 12
cycles.
(D) FOLFIRINOX protocol (Oxaliplatin +
Irinotecan + Fluorouracil). Day 1: oxaliplatin 85 mg/m2 IV
over 2 hours, Irinotecan 180 mg/m2 IV over 90 minutes,
Leucovorin 400 mg/m2 IV over 90 minutes, followed by
Fluorouracil 400 mg/m2 IV push, followed by Days 1-2,
Fluorouracil 1,200 mg/m2 IV continuous infusion over 24 hours
(2,400 mg/m2 IV over 46 hours). Repeat cycle every
2 weeks for a total of 12 cycles.
Data collection
Before data collection, oral
consent was taken from patients. Clinical data were collected by a
questionnaire and it included age, gender, diagnosis (colon, pancreas, rectum,
stomach), history of chronic disease (diabetes mellitus, hypertension, neuropathy,
none), treatment protocol (XELOX, FLOT, FOLFOX, FOLFIRINOX), degree of pain
severity, cancer stage (TNM), history of previous vascular pain, number of
cycles, the incidence of vascular pain, oxaliplatin dose. Pain assessment was
done by visual analog scale (VAS).
The visual analog scale (VAS) is a validated, subjective measure for
acute and chronic pain. Scores are recorded by making a handwritten mark on a
10-cm line that represents a continuum between "no pain" and
"worst pain" (Delgado et al., 2018).
Inclusion / exclusion criteria
Included
in the study were patients between the age of 18 and 80 years, patients
diagnosed with colon, pancreatic, rectal, and
stomach cancer, and patients receiving
oxaliplatin peripheral venous infusion. Excluded from the study were patients
less than 18 years and more than 80 years, having a vascular disease other than
malignancy (ex: severe atherosclerosis and deep venous thrombosis (DVT), and
patients with central line port.
Ethical considerations
Ethical approval was obtained
from the Ethics Committee of Al-Andalus Private Hospital for Cancer Patients,
Baghdad, Iraq. All patients gave their informed consent before their inclusion
in the study.
Statistical analysis
Data of all patients were
entered and managed using the Statistical Package for Social Sciences (SPSS)
software (version 25). Descriptive analysis for quantitative data included
median and interquartile range instead of mean and standard deviation due to
violation of normal distribution.
For qualitative categorical variables, frequency and percentage were
applied. A test of significance for each baseline characteristic variable has
been done to check for study sample randomization within each characteristic
category. A multivariate logistic
regression model has been done to adjust for that significant difference. The
statistical analysis was based on a two-tailed test using a level of
significance for analysis at p ² 0.05.
Relation between severity of
pain, age, & gender is presented in Table
5. The age group from 40-60 years old was significantly associated with 59
% higher odds of vascular pain induction during oxaliplatin administration
(OR=1.59, CI: 1.07 - 2.39) than other age groups. Female patients were
significantly associated with 59 % higher odds of vascular pain induction
during oxaliplatin administration (OR=1.59, CI: 1.07 - 2.39) than males.
Discussion
Mild to moderate vascular pain
originating around the injection site during peripheral intravenous
administration of oxaliplatin is a significant problem. We carried out this
cross-sectional observational study at Al-Andalus Private Hospital for Cancer Patients,
Baghdad, Iraq between the period of October 2020 and April 2021. The study
included 101 patients, diagnosed with one of the following cancers: colon,
pancreatic, stomach cancer, and rectal, between the ages of 18 and 80, and
receiving oxaliplatin peripheral
venous infusion.
In our study, sixty-two
patients out of 101 patients had experienced vascular pain during oxaliplatin peripheral venous infusion,
representing about (61.4 %). In a
study carried out by Yoshida et al., vascular pain developed in 34 patients
(72.3 %) out of 47 patients who received XELOX + bevacizumab therapy for
metastatic colorectal cancer (Yoshida et al.,
2012). In comparison to oxaliplatin-induced peripheral neuropathy, a study
carried out by Ali et al. reported that the acute and chronic incidence of
oxaliplatin-induced peripheral neuropathy among 121 patients at Khartoum
Oncology Hospital was found to be
49.6 % and 41.3 % respectively (Ali et al., 2020).
In our study, there was no
statistically significant difference between the study protocols regarding neither
vascular pain induction nor the degree of severity of induced pain. On the
other hand, in a multicenter study of the Yokohama Clinical Oncology Group
(YCOG) in Japan, it was reported that the rate of grade ³ 2 vascular pain was
55.3 % in the group receiving Capeox (capecitabine and oxaliplatin) therapy
only and 53.8 % in the group receiving Capeox therapy (capecitabine and
oxaliplatin) with 400 mg/day of celecoxib (p = 1.000) (Suwa et al., 2019).
In our study, only a history
of diabetes mellitus was significantly associated with vascular pain induction
(OR=1.59, [CI: 1.07 - 2.39])). In addition, there was no statistically
significant association between administered oxaliplatin dose and vascular pain
induction. Comparatively, in a study carried out by Suga et al., it was
reported that BMI (BMI < 22), clinical-stage (I-III), and oxaliplatin dosage
(130 mg/m2 versus dose reduction) were identified as independent risk factors
for the development of vascular pain (Suga et al., 2018). Moreover, Takagi et al. have reported that oxaliplatin dosages of more
than 175 mg/body are significantly related to the development of vascular pain,
suggesting that vascular pain is more likely to occur at higher oxaliplatin
dosages (Takagi A, 2015).
In our study, the age group
from 40-60 years old was significantly associated with 59 % higher odds of
vascular pain induction during oxaliplatin administration (OR=1.59, CI: 1.07 -
2.39) than other age groups. Moreover, female patients were significantly
associated with 59 % higher odds of vascular pain induction during oxaliplatin
administration (OR=1.59, CI: 1.07 - 2.39) than males. In a study carried out by
Kawazoe et al., multivariate logistic regression analysis revealed that the
female gender was significantly associated with an increased risk of venous
pain during all courses of oxaliplatin treatment (Kawazoe, 2017). On the other hand, when compared to oxaliplatin-induced peripheral
neuropathy, Mizrahi et al. reported that also older age (_ = 0.08; 95% CI, 0.06
to 0.11; P < .001), and female gender (_ = _1.08; 95% CI, _1.76 to _0.16; P
= .01) were associated with worse peripheral neuropathy pain (Mizrahi et al., 2021).
This
study can be evaluated in terms of its strengths and limitations. To our
knowledge, this study was the first to focus on vascular pain caused by
oxaliplatin in Iraq. A limitation of this study was that pain prevalence was
underestimated because it was mild pain so we need prospective trials with
close monitoring of the patients during infusion. Another limitation is that in
this study we used oxaliplatin from one manufacturer due to its sole
availability; therefore, we need to do comparative observational studies
between different manufacturing pharmaceutical companies.
Conclusion
The results of this study
indicate that history of diabetes mellitus, the age group from 40-60 years old,
and female gender are risk factors for oxaliplatin-induced vascular pain in
patients with GI malignancy. These findings could be useful to assess the risk
of vascular pain in clinical settings. Based on the results of this study
together with previous findings, we suggest that the best option for the management
of oxaliplatin-induced vascular pain may be carefully timed.
Conflict of Interest Statement:
The authors declare that they
have no conflict of interest.
Ethics Statement:
Ethical approval was obtained
from the Ethics Committee of Al-Andalus private hospital for cancer patients,
Baghdad, Iraq. All patients gave their informed consent before their inclusion
in the study.
Financial Support: None
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