Download Title : Prevention of neuropathy induced by

Title : Oxaliplatin-induced neuropathy in subjects with colorectal cancer.
Authors:
R. Dault. MSc*, M-P. Rousseau. MSc.†, A. Beaudoin. MD‡, M-A. Frenette. B.Sc
§
., F. Lemay. MD‡, M-F. Beauchesne. Pharm.D||.
*Département de médecine familiale, Faculté de Médecine et des Sciences de la
santé, Université de Sherbrooke, Sherbrooke, Qc, Canada.
†Département de pharmacie, Centre Hospitalier Universitaire de Sherbrooke
(CHUS), Sherbrooke, Qc, Canada.
‡CHUS, Faculté de Médecine et des Sciences de la santé (FMSS), Université de
Sherbrooke, Centre de recherche du CHUS (CR-CHUS), Sherbrooke, Qc,
Canada.
§
Faculté de droit, Université de Sherbrooke, Sherbrooke, Qc, Canada.
|| Département de pharmacie, CHUS, FMSS, Université de Sherbrooke, Faculté
de pharmacie, Université de Montréal, CR-CHUS, Sherbrooke, Qc, Canada.
Short-title: Oxaliplatin-induced neuropathy.
Correspondance: Marie-France Beauchesne, département de pharmacie,
Centre Hospitalier Universitaire de Sherbrooke, Hôpital Fleurimont, 3001, 12 ème
avenue Nord, Sherbrooke, Québec, Canada, J1H 5N4. Ph : 514-343-2154.
Email : [email protected]
Acknowledgment of grant support: The research team has received an
unrestricted grant from Sanofi Canada for the conduct of this investigator-initiated
project.
This project was presented at the annual ISOPP meeting (Montreal, May 2014).
Word count : 1281 words.
Number of tables : 2
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Abstract
Oxaliplatin plays a major role in the treatment of colorectal cancer (CRC) but is
associated with the development of neuropathies. The main objective of this
project was to estimate the proportion of subjects with grade 1, 2, 3 or 4
neuropathies according to the NCI_CTC (version 4) criteria, in CRC subjects
treated with oxaliplatin (adjuvant or metastatic) at the Centre hospitalier
universitaire de Sherbrooke (CHUS). A total of 57 patients were included.
Maximal grade 2 neuropathy was reported by about 60% of patients during
treatment. Near 25% of patients had to stop treatment because of neuropathies.
In a subset of patients reached approximately 22 months following treatment
cessation, neuropathies persisted in 70% of cases. Oxaliplatin-induced
neuropathy affects a significant number of CRC patients and can influence the
course of treatment and outcomes.
Key words: colorectal cancer, oxaliplatin, neuropathy.
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Introduction
Colorectal cancer (CRC) is one of the three most common cancers in North
America.1 Oxaliplatin is frequently used for CRC management in the adjuvant or
metastatic setting, and peripheral neuropathy is a dose-limiting effect of this
treatment.2 Previous studies have reported incidences up to 50% for grade 2 or
worse neuropathy, and up to 20% for grade 3 or worse neuropathy, but patients
with medical conditions or concomitant use of medications that could influence
the level of severity of neuropathy were generally excluded. 3-5
The incidence and severity of neuropathy along with its impact on the course of
treatment is currently unknown in our patient population. Therefore, we
conducted this explorative study to describe the presence of chronic peripheral
sensory neuropathy in oxaliplatin-treated CRC patients and how it influences the
course of treatment at our institution.
Methods
A prospective study was conducted at the Centre Hospitalier Universitaire de
Sherbrooke (CHUS), an academic tertiary care center in Canada. Included
subjects had a diagnosis of CRC, were older than 18 years, and newly treated
with oxaliplatin using the FOLFOX or XELOX type regimens in the adjuvant or
metastatic setting. Patients were recruited between May 2012 and April 2013.
The ethics committee of our institution approved this project and all participants
signed a written consent form.
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The main objective of this study was to estimate the proportion of CRC subjects
reporting maximum grade 1, 2, 3 or 4 chronic peripheral sensory neuropathies,
according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC
version 46) during oxaliplatin treatment. We also contacted a subset of subjects
who were treated in the adjuvant setting, who had peripheral neuropathies while
on treatment, about 24 months following the last treatment to assess the
persistence of chronic peripheral sensory neuropathy. Secondary objectives
were to estimate the cumulative dose of oxaliplatin, the number of cycles
received, along with the number of patients with oxaliplatin dose reductions,
treatment delays and treatment cessation, all because of neuropathies.
Subjects on the mFOLFOX type regimen were scheduled to receive oxaliplatin
every 2 weeks, while subjects on XELOX were scheduled to receive oxaliplatin
every 3 weeks. In the adjuvant setting, the number of cycles planned at baseline
was of 12 (about 6 months) while in the metastatic setting, treatments with
oxaliplatin were continued until disease progression or intolerance.
Subjects completed the questionnaire on peripheral sensory neuropathies with a
research assistant at baseline and before each oxaliplatin treatment (maximum
follow-up of 12 months on treatment). During the study, the protocol was
amended to contact a subset of subjects who received oxaliplatin in the adjuvant
setting, about 24 months following the end of treatment, to inquire about the
persistence of neuropathy. Based on previous numbers of oxaliplatin-treated
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CRC subjects at our center (about 96 in the year 2011), we expected to recruit
about 75 subjects in our study to provide an accurate estimate of the proportion
of subjects with chronic peripheral sensory neuropathies.
The FACT&GOG-Ntx-12 (Version 46) questionnaire was used to estimate the
presence of chronic sensory neuropathy. This tool includes 12 questions
regarding the presence of sensory neuropathy in the last 7 days. Peripheral
sensory neuropathy was then graded according to the NCI-CTC version 4 with
grade 1 being a loss of deep tendon reflexes or paresthesia; grade 2: objective
sensory loss or paresthesia interfering with function; grade 3: sensory loss or
paresthesia interfering with activities of daily living; grade 4: permanent sensory
loss that interferes with function.
Patient characteristics are described by age, gender, type of CRC treatment (ie.
FOLFOX or XELOX type regimen), type of CRC (ie. Adjuvant, metastatic or
metastatic resected), and the presence of selected co-morbidities (ie. Chronic
pain, fibromyalgia, neuropathic pain before oxaliplatin therapy, diabetes,
rheumatoid arthritis, multiple sclerosis, chronic renal insufficiency). Furthermore,
we describe the use of concomitant medications during oxaliplatin therapy that
can influence the level of general pain or neuropathic pain (ie. Acetaminophen,
nonsteroidal
anti-inflammatory
drugs,
opioids,
topical
anesthetics,
antidepressants and anticonvulsants). Descriptive statistics were estimated with
proportions for the maximal grade for sensory peripheral neuropathy, and means
for cumulative dose, number of cycles, dose reductions, treatment delays and
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treatment cessations, all because of chronic peripheral sensory neuropathy. Data
for patients who died or were lost to follow-up were included in the analysis.
Results
Fifty-seven patients were included; five patients with metastatic CRC died while
on treatment during follow-up, no other subjects were lost to follow-up. Baseline
characteristics of subjects and oxaliplatin treatments are outlined in table 1. Most
subjects were prescribed a FOLFOX type regimen; the stop-and-go approach
was used in 5 patients with metastatic CRC. Fifteen patients (26%) had a
comorbidity of interest documented in medical charts or reported by the patients
and 38 (67%) were prescribed a medication that could influence pain or
neuropathy. Main results are presented in table 2. About 95% reported
neuropathies during treatment with oxaliplatin and nearly 60% had maximum NCI
grade 2 neuropathies. Treatment was stopped prematurely in 8 patients on
adjuvant therapy and 6 metastatic patients (including 2 on the stop-and-go
approach) because of neuropathies and oxaliplatin-dose was reduced for 15
patients (9 adjuvant, 5 metastatic, 1 metastatic resected) because of
neuropathies. No treatments were delayed due to the presence of neuropathies.
From the 29 subjects treated in the adjuvant setting, 13 agreed to be contacted
about 24 months following treatment cessation to inquire about the persistence of
neuropathies; one patient was lost to follow-up, one died and one was excluded
from the analysis because he did not report neuropathies while on treatment.
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Thus, a total of 10 subjects were evaluated for persistent neuropathies, about 22
months following oxaliplatin cessation (range between 16 and 28 months posttreatment cessation); 7 (70%) of them had persistent neuropathies (grade 1: 4
subjects; grade 2:2 subjects; grade 3: 1 subject).
Discussion and conclusions
This study allowed us to describe our CRC population on oxaliplatin and how
chronic peripheral sensory neuropathy influences the course of treatment.
Oxaliplatin induced maximum grade 2 peripheral neuropathies in most patients
who experienced this side effect while on treatment. Overall, about 77% of
subjects had sensory peripheral neuropathy of grade 2 or more, which is higher
than expected, and could be explained by the fact that previous studies have
excluded patients with concomitant comorbidities that could influence this
outcome. While the number of subjects reached following treatment cessation
was limited, our results suggest that neuropathies persist several months after
treatment discontinuation.
Park et al. assessed oxaliplatin-induced neuropathy in a group of 108 patients
(on the FOLFOX or XELOX type regimens), using the neuropathy sensory
subscale of the NCI CTCAE scale (version 3).7 The mean cumulative dose of
oxaliplatin received by the patients included was of 802.8mg/m2 (vs 697,3 in our
study). The proportion of patients with Grade 2 maximum neuropathies was of
41.6% (vs 57.9% in our study). About 30% of subjects (vs 26.3% in our study)
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had dose reductions and 33% (vs 24.6%) had premature treatment cessations
because of neurotoxicity. In the Park et al. study, most patients (79.2%) reported
persistent neuropathic symptoms at long-term follow-up (ie. median of 29 months
post-oxaliplatin). In our study, many patients treated in the adjuvant setting did
not reach the targeted number of cycles of oxaliplatin. These results highlight the
impact of chronic peripheral sensory neuropathy on the course of oxaliplatin
treatment.
Our study included a small number of patients and was conducted in a single
center, which limits generalization of the results. Furthermore, we did not
correlate cumulative dose with the occurrence of degree of neuropathy
considering the low number of subjects included. However, it is well know that
oxaliplatin-induced neuropathy is dose-related. Our results are limited, but
underline the importance of further studies on various strategies to minimize
oxaliplatin-induced neuropathy.
Acknowledgments and Conflict of interests’ disclosure:
We have read and understood Current Oncology’s policy on conflicts of interest
disclosures and declare the following interests:
AA and FL have received speaker fees from Sanofi company.
The research team received funding from Sanofi company for the conduct of this
investigator initiated trial.
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References
1. Siegel R, Ma J, Zou Z, Jernal A. Cancer statistics, 2014. CA Cancer J Clin.
2014;64:9–22.
2. Beijers AJ1, Mols F, Vreugdenhil G. A systematic review on chronic
oxaliplatin-induced peripheral neuropathy and the relation with oxaliplatin
administration. Support Care Cancer. 2014;22:1999-2007. doi:
10.1007/s00520-014-2242-z. 3.
3. Grothey A, Nikcevich DA, Sloan JA, et al. Intravenous calcium and
magnesium for oxaliplatin-induced sensory neurotoxicity in adjuvant colon
cancer: NCCTG N04C7. J Clin Oncol. 2011;29:421-7.
4. Allegra C. J., Yothers G, O’Connell M. J., et al. Initial safety report of NSABP
C-08: a randomized phase III study of modified FOLFOX6 with or without
bevacizumab for the adjuvant treatment of patients with stage II or III colon
cancer. J Clin Oncol. 2009; 27: 3385–3390.
5. De Gramont A, Fige A, SeymourM, et al. Leucovorin and fluorouracil with or
without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin
Oncol. 2000; 18: 2938–2947.
6. FACIT. National Cancer Institute Common Terminology Criteria for Adverse
Events (CTCAE) Version 4.03; 2010. [Available at: www.facit.org. Cited June
3, 2015].
7. Park SB, Lin CS, Krishnan AV, Goldstein D, Friedlander ML, Kiernan MC.
Long-term neuropathy after oxaliplatin treatment : challenging the dictum of
reversibility. Oncologist. 2011;16:708-16. doi: 10.1634/theoncologist.20100248.
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Table 1: Baseline characteristics
Characteristic
All (n=57)
Age, median (range)
66 (43-84)
Gender, males n (%)
33 (57.9)
Oxaliplatin-type regimen, n (%)
FOLFOX
55 (96.5)
XELOX
2 (3.5)
Type of CRC, n (%)
Adjuvant
29 (50.9)
Metastatic-non resected
20 (35.1)
Metastatic-resected
8 (14.0)
Co morbidities, n (%)
Chronic pain
9 (15.8)
Type 2 diabetes
6 (10.5)
Chronic renal impairment
3 (5.3)
Rheumatoid arthritis
1 (1.8)
Neuropathic pain
1 (1.8)
Fibromyalgia
0
Multiple sclerosis
0
Concomitant medication, n (%)
Acetaminophen
30 (52.6)
Opioids
15 (26.3)
Antidepressants1
8 (14.0)
Anticonvulsants2
8 (14.0)
Nonsteroidal anti-inflammatory agents
7 (12.3)
Topic analgesic3
5 (8.8)
Cannabinoids4
1 (1.8)
1.Antidepressants: Paroxetine, Citalopram, Mirtazapine, Nortriptyline, Venlafaxine
2.Anticonvulsants: Carbamazepine, Gabapentin, Lamotrigine, Pregabalin
3.Topical analgesic: Lidocaine, Lidocaine and Prilocaine
4.Cannabinoids: Nabilone
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Table 2: Main results
Adjuvant
N=29
Metastatic,
non resected
N=20
671.21 (314.7)
Metastatic,
resected
N=8
944.01 (197.6)
TOTAL
N=57
Cumulative
647.3 (243.6)
697.3 (279.9)
dose, mg/m2,
mean (SD)
Numbers of
7.9 (3.2)
7.5 (3.6)
10.8 (2.1)
8.2 (3.3)
cycles,
mean (SD)
Dosage
9 (31.0)
5 (25.0)
1 (12.5)
15 (26.3)
reductions
because of
9 treatments
8 treatments
2 treatments
19 treatments
neuropathy,
n of subjects
(%)
Treatment
8 (27.6)
6 (30.0)
0
14 (24.6)
cessations
because of
neuropathy,
n of subjects
(%)
Maximal
3 (10.3)
4 (20.0)
3 (37.5)
10 (18.2)
grade 1
neuropathy
during
treatment, n of
subjects (%)
Maximal
18 (62.1)
11(55.0)
4 (50.0)
33 (57.9)
grade 2
neuropathy
during
treatment, n of
subjects (%)
Maximal
6 (20.7)
5 (25.0)
0
11 (19.2)
grade 3
neuropathy
during
treatment2, n
of subjects
(%)
1. At 12 months
2. Three patients had no neuropathy and none reported grade 4 peripheral
sensory neuropathies.
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