Download Epidermal growth factor receptor – inhibition (EGFR

British Journal of Anaesthesia, 115 (5): 761–7 (2015)
doi: 10.1093/bja/aev326
Pain
PAIN
Epidermal growth factor receptor – inhibition (EGFR-I)
in the treatment of neuropathic pain
1
Center for Cancer Treatment, Sørlandet Hospital, Pb 416, Kristiansand 4604, Norway, 2Edinburgh Cancer
Research Centre, University of Edinburgh, Edinburgh EH4 2XR, UK, and 3European Palliative Care Research Centre,
NTNU, Trondheim, Norway
*Corresponding author. E-mail: [email protected]
Abstract
Background: Neurobiological work has demonstrated that expression of mitogen-activated protein kinases (MAPK) is
upregulated on neurones and glial cells after nerve damage. Furthermore, the epidermal growth factor receptor (EGFR) has been
identified as having a key role in this process and subsequent interruption of this using EGFR-Inhibitors (EGFR-I), may improve
neuropathic pain. The aim of this report was to explore if EGFR-I attenuated neuropathic pain in humans.
Methods: A selection of patients with neuropathic pain were treated off-label with one of four EGFR-Is, approved for the
treatment of cancer. All patients had chronic and severe neuropathic pain (as defined by diagnostic criteria). Pain intensity,
interference with function, and adverse events were prospectively registered.
Results: Twenty patients were treated. Eighteen patients experienced clinically significant pain relief after treatment with
EGFR-I. Median observed pain reduction for all patients was 8.5 (IQR=5–9.5) points on a 0–10 numeric rating scale. Neuropathic
pain spike duration and frequency also improved. Pain relief was most often achieved within 24 h and was more rapid in cases of
i.v. than oral administration. All four EGFR-I that were tested were of equal efficacy. The duration of pain relief was consistent
with the individual drugs’ half-lives. No cases of drug-tolerance were observed. Side-effects were predominantly skin reactions.
One grade 3 adverse event was registered. Median follow-up for responders was 7 months (Range 1–37).
Conclusions: EGFR-I improves neuropathic pain and this is in keeping with basic science work. Controlled clinical trials are now
eagerly awaited to assess this further.
Key words: analgesics; epidermal growth factor; neuralgia; pain, radiating; receptor
Neuropathic pain is defined as ‘pain caused by a lesion or disease
of the somatosensory nervous system’.1 The genesis of neuropathic pain is varied but commonly affects patients with diabetes, peripheral vascular disease and cancer, resulting in
millions of patients being affected worldwide. The pathophysiology of neuropathic pain is complex and if the initial nervous
system damage does not resolve, a combination of ectopic
nerve discharge combined with altered architecture of the pain
pathways within the dorsal horn of the spinal cord, leads to a
state of central sensitization.2 This aggravates chronic pain,
which when it is of neuropathic origin, is widely accepted as
being more difficult to treat than other types of pain.3 Chronic
neuropathic pain, in turn, is associated with anxiety, depression
and reduced quality of life which, in combination with the economic impact that it has, makes it a major health concern.4–6
Adjuvant analgesics such as anticonvulsants and antidepressants are an important part of the treatment of neuropathic
pain.7 However, the most widely-used adjuvant analgesics in
† Authors contributed equally.
Accepted: July 20, 2015
© The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
For Permissions, please email: [email protected]
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C. Kersten1,†,*, M. G. Cameron1,†, B. Laird2,3 and S. Mjåland1
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| Kersten et al.
Editor’s key points
• Neuropathic pain remains a clinical problem.
• Inhibition of epidermal grown factor receptor (EGFR) may be
useful.
• In this case series, 20 patients were treated with an EGFR
inhibitor.
• Eighteen patients had clinically relevant pain relief after
treatment.
• Randomized controlled clinical trials of an EGFR inhibitor
are warranted.
report information on their neuropathic pain only. The brief
pain inventory, short form was used pre/post treatment in
order to quantify pain severity and interference and thus help
guide clinical decision-making.20 This was not performed at
standardized time points, as patients were treated according to
their individual clinical courses, as medically indicated, outside
of a clinical trial. For the same reason, only routine blood tests,
obtained in order to monitor side-effects, were assessed. The
global impression of change scale21 was used as a supplement
in selected cases, when the other scales were lacking in their
description of the temporal aspects of pain.
Treatment
Methods
Overview
Nineteen patients were treated at a regional cancer centre in
Norway (Sørlandet Hospital). Off-label use of EGFR-I for the treatment of neuropathic pain in these patients was approved by the
hospital’s ethics committee. One patient was treated at a different hospital. All patients or next of kin gave written consent for
the publication of their anonymized data.
Eligibility
All patients had neuropathic pain which was not controlled with
standard therapies. Neuropathic pain was defined using the
grading system introduced by Treede and colleagues18 for clinical
and research purposes. Radiological imaging confirmed the
offending lesion whenever possible. The painDETECT questionnaire was used to support the diagnosis of neuropathic pain;
with scores ≥18 indicating a 90% likelihood of neuropathic pain.19
Assessments
Before starting treatment, pain intensity was assessed using a
0–10 numerical rating scale which specified, among other aspects
of pain, the worst degree of neuropathic pain in the preceding
24 h. If patients had several types of pain, they were asked to
Four of 20 patients were given EGFR-Is with the intention to treat
their cancer. The remaining 16 patients were treated with EGFRIs specifically to treat neuropathic pain. Patients were initially
given standard, oncologic doses of the following EGFR-Is: cetuximab 250 mg m−2 after a loading dose of 400 mg m2−1; panitumumab 6 mg kg−1; gefitinib 250 mg; or erlotinib 100–150 mg. Doses
were then adjusted as clinically indicated. Tetracycline (500 mg
orally twice daily), topical steroids and moisturizers were used
to prevent or treat dry skin and acneform rash, which are frequent side-effects of EGFR-I. After the expected peak of skin
changes (approximately 8–10 weeks), an attempt was made to
decrease or stop the use of these agents.
Analysis
Findings were summarized and presented using descriptive statistics. More descriptive information about the individual cases,
their specific treatments, the quality of pain relief and its impact
on QOL and function, and toxicities can be found in the Online
Supplementary data. Case numbers represent the chronological
order in which the patients were treated.
Results
Twenty patients with neuropathic pain were treated with EGFRIs. Patient characteristics and pre-treatment pain characteristics
for all 20 patients are presented in Table 1.
Eleven (55%) patients were male and the median age was 59
(mean 56, range 24–77) years. The median PainDETECT score
was 23 (range 16–31). The most common aetiologies of neuropathic pain were cancer (n=7, 35%) and benign radiculopathies
(n=5, 25%). The median duration of neuropathic pain was eight
(range 0.5–84) months suggesting it was chronic rather than
acute. All patients characterized their pain as severe and scored
≥7 on a 0–10 NRS. The median worst pain score was 9 (IQR=8.5–
10). Treatment characteristics and responses for all 20 patients
with neuropathic pain are summarized in Table 2.
Eighteen patients reported clinically meaningful improvement in neuropathic pain (defined as a ≥2 point decrease on a
0–10 numerical rating scale for worst pain in the last 24-h).22
after treatment with EGFR-Is. The median improvement in
worst pain score within four weeks of initial treatment was 8.5
(IQR=5–9.5) and pain relief was maintained for as long as the patients stayed on EGFR-Is, the median duration of which was
seven months (range=0.5–47) to date.
Figure 1– shows changes in worst pain scores for individual
patients, grouped according to aetiology of the neuropathic pain,
from initial treatment to day 13 post-treatment. As demonstrated,
across all the different pain aetiologies, EGFR-I administration
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neuropathic pain (amitriptyline and gabapentin) require treatment of approximately three to five patients, respectively, in
order to achieve clinically meaningful pain reduction in one patient.7 Newer adjuvant analgesics need even higher numbers for
one patient to benefit. Furthermore, adjuvant analgesics, either
alone or in combination with opioids, may result in unacceptable, especially central nervous system, side-effects, which
might hinder their use.8–10 Given the limited efficacy of existing
therapies for neuropathic pain, there is a need to explore other
treatment options.
We have previously reported clinically significant improvement in neuropathic pain in five of six patients using epidermal
growth factor receptor inhibitor (EGFR-I).11 12 The EGFR is a member of the ErbB family of four different receptor tyrosine kinases
and has been implicated in the development of epithelial cancers.13 Consequently, (EGFR-I) were developed and are approved
for the treatment of colorectal, lung, ear-nose-throat and pancreatic cancers.14–17
After these preliminary clinical observations, we have treated
a further 14 patients who had neuropathic pain, with EGFR-Is. We
present follow-up of the previously-reported cases and provide a
comprehensive overview of all 20 patients treated with EGFR-I for
neuropathic pain as a result of cancer or other conditions.
Epidermal growth factor receptor inhibition
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Table 1 Patient characteristics and pre-treatment pain characteristics. CIPN, chemotherapy induced peripheral neuropathy; CRPS, complex
regional pain syndrome; EGFR-I, Epithelial growth factor receptor inhibitor; IQR, interquartile range; ND, not done. 1PainDETECT scores
range 0–38. 2referring to neuropathic pain only, assessed by numeric rating scale. 3including failed back surgery and other causes of benign
sciatica
Number of
cases, (n)
Age mean
(range), yr
PainDETECT Scores1,
Median (range)
Neuropathic pain
duration before EGFR-I,
Median (range), months
‘Worst pain’2 score
before EGFR-I,
Median (IQR)
Cancer-related neuropathic pain
Benign radiculopathy3
CIPN
Acute herpes zoster
Post herpetic neuralgia
Phantom limb pain
CRPS type I
Idiopathic peripheral neuropathy
Summation of cases
7
5
2
1
1
2
1
1
20
52 (25–68)
54 (41–72)
63, 67
77
77
24, 72
53
54
56 (24–77)
24 (16–25)
23 (16–28)
19, 23
ND
19
16, ND
31
30
23 (16–31)
5 (1–24)
8 (5–10)
24, 24
0.5
26
11, 84
8
72
8 (0.5–84)
10 (9–10)
9 (7–9.5)
8, 8
10
10
8.5
10
9
9 (8.5–10)
Table 2 Treatment characteristics and results. A, anticonvulsants; AD, antidepressants; AI, antiinflammatories; O, opiates; C, cetuximab;
E, erlotinib; G, gefitinib; P, panitumumab; NA, not applicable; IQR, interquartile range. 1Defined as improvement of worst pain on numerical
rating scale of >2 points; 2pain relief observed for as long as all the responding patients stayed on the drug. 3including failed back surgery or
other benign causes of sciatica; *Numerical rating scale for pain unable to convey reduced frequency and duration of pain attacks, see text
Aetiology of neuropathic pain
Number of cases
reporting pain
relief1/number of
cases treated
Analgesics
reduced by more
than 50% within
4 weeks
EGFR-Is tested &
effective
Reduction in
‘worst pain’ score
within 4 weeks,
Median (IQR)
Observed pain
relief 2, Median
[range] (months)
Cancer-related
Benign radiculopathy3
CIPN
Acute Herpes Zoster
Post herpetic neuralgia
Phantom limb pain
7/7
5/5
2/2
1/1
1/1
1/2
O, A, AI
O, A, AI
A, AI
O, AI
AD, AI
O
10 (10–10)
7 (5–9)
4*
10
3*
0, 5
7 [4–47]
9 [0.5–14]
3.5, 12
5
15
1, 3
CRPS type I
Idiopathic peripheral neuropathy
Summation of all 20 cases
1/1
0/1#
18/20
O, A, AI
NA
O, A, AI, AD
C, E, P
C, E, G, P
E, P
E, P
E, P
E, P one nonresponder (P)
C, E, G, P
non-responder (C)
C, P, G, E
9.5
0
8.5 (5–9.5)
37
NA
7 [0.5–47]
resulted in an improvement in neuropathic pain by at least 2 points
on the rating scale.
analgesics, including opiates, during the further courses of
their illnesses. However, the use of opiates and other analgesics
was able to be reduced in all cases (Table 2).
Malignant neuropathic pain (n=7)
In seven of the 20 cases, neuropathic pain was a result of radiologically confirmed malignant infiltration of nerves. In two of
the cancer patients, relief of neuropathic pain was a serendipitous finding, as EGFR-I was given to target the underlying cancer
rather than the pain itself. In six of the seven patients, worst pain
scores decreased from 8–10 to 0 within the first 24-h period. The
only cancer patient whose score did not reach 0 within 24-h was
unable to completely differentiate neuropathic pain from concomitant pain from widespread skeletal metastases (Fig. 1).
Before EGFR-I, all of the cancer patients reported severely disturbed sleep, impaired quality of life and reduced functional status because of their neuropathic pain. These functions improved
within the first week after treatment. As the cancer patients all
had widespread, metastatic disease, they also had symptoms
outside the pelvis, including non-neuropathic pain. No patients
reported improvement in other types of pain after treatment
with EGFR-I. Consequently, they required other forms of
Benign neuropathic pain (n=13)
Thirteen patients had neuropathic pain as a result of benign conditions (Fig. 1 + ). Pain reduction after EGFR-I administration was as
rapid and almost as complete for patients with benign radiculopathies, (Fig. 1), complex regional pain syndrome type 1 (CRPS-I) and
acute herpetic neuralgia (Fig. 1), as it was for patients with cancer.
However, the maximum effect in patients with chemotherapy induced peripheral neuropathy and post-herpetic neuralgia was
more gradual (Fig. 1), and was maximal within three to four
weeks. After rapid onset of pain relief, several patients increased
their physical activity abruptly (Fig. 1 and ; Cases 4, 6 and 15)
leading to muscular pain. The time of onset for best response varied according to the mode of drug administration with i.v. administered drugs resulting in a more rapid onset than oral formulations
(case 10 Fig. 1; and case 4 reported previously12).
In patients whose pain manifested primarily as pain flares, the
rating scale did not adequately capture the degree of pain relief
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Aetiology of neuropathic pain
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| Kersten et al.
Cancer
A 10
8
6
4
11 RCC
14 RC
2
1 RC 5 BC 12 RC 20 CC
1
2
3
4
5
6
7
8
9
10
11
12
8
Worst pain score
13
Benign radiculopathy
B 10
19
6
7
4
4
15
2
10
1
2
3
4
5
6
7
8
Other causes of NP
9
10
11
12
13
C
8 CIPN
8
3 CRPS
6
16 CIPN
6 PLP
18 PHN
4
2
9 HN
0
1
Days
2
3
4
5
6
Cetuximab (iv)
7
8
9
10
Panitumumab (iv)
11
12
13
Erlotinib (po)
EGFR-I’s used
Fig 1 (–) Changes in worst pain scores for individual patients, grouped according to aetiology of the neuropathic pain. Worst pain scores for individual patients pretreatment (day 0) and for the first 13 post–treatment days. Numbers in the figures indicate case numbers, reflecting the order in which the patients were treated (see
appendix). BC, bladder cancer; CC, cervical cancer; RCC, renal cancer; RC, rectal cancer; CIPN, chemotherapy (oxaliplatin) induced peripheral neuropathy; CRPS,
complex regional pain syndrome type 1; HN, acute Herpes Zoster; PHN, post-herpetic neuralgia; PLP, phantom limb pain; PN, idiopathic peripheral neuropathy.
See appendix for detailed narrative according to case numbers.
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13 RC
Epidermal growth factor receptor inhibition
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Time to pain recurrence
EGFR-I:
Case 4 (FBSS)
Case 9 (HN)
Panitumumab
Case 12 (RC)
Case 20 (CC)
Case 1 (RC)
Cetuximab
Case 4 (FBSS)
Case 3 (CRPS)
Gefitinib
Cetuximab (iv)
Panitumumab (iv)
Case 16 (CIPN)
Gefitinib (po)
Erlotinib (po)
Case 19 (FBSS)*
0
5
10
15
Days since last dose
20
25
Fig 2 Time to neuropathic pain recurrence after stopping EGFR-I. Panitumumab (blue bar) has an elimination half-life of 7.5 days (range: 3.6–10.9 days) [28] and its
recommended administration interval is 14 days when given as an anti-cancer drug. The elimination half-life of cetuximab (green bar) ranges from 2.9 to 4.2 days
[35] and for oncologic indications the drug is given every 7 to 14 days. For the oral agents, the elimination half-lives are 36 and 41 h for erlotinib (orange bar) [25] and
gefitinib ( pink bar) [24], respectively. FBSS, failed back surgery syndrome; HN, herpetic neuralgia; RC, rectal cancer; CC, cervical cancer; CRPS, complex regional pain
syndrome type 1; CIPN, chemotherapy-induced peripheral neuropathy; *dose reduction of erlotinib from 150 to 100 mg.
Table 3 Adverse events
Adverse Events for all
EGFR-I
Skin changes
Allergic reactions
Diarrhoea
Stomatitis
Dyspnoea
Infection
Opioid overdose and/or opioid
withdrawal syndrome
Hypomagnesaemia
Dysgeusia
Alopecia
Aseptic meningitis
Elevated liver enzymes
Nausea
Hypertrichosis
Grade 1 or
2, n (%)
Grade 3 or
4, n (%)
16 (80)
0
2 (10)
1 (5)
0
1 (5)
3 (15)
0
0
0
0
0
0
0
3 (15)
1 (5)
1 (5)
0
1 (5)
1 (5)
2 (10)
0
0
0
1 (5)
0
0
0
Patients were told to contact one of the treating physicians when
they felt that their pain returned. Patient-reported time to pain
recurrence was consistent with pharmacokinetics of all four
types of EGFR-I used.
Adverse events
Table 3 shows the adverse events (AE) recorded in routine clinical
follow-up. The most frequent AEs observed were transient skin
changes, none greater than grade 2. All but two of the patients
were treated with prophylactic tetracycline from around the
time the EGRF-I was initiated. Four patients experienced mild to
moderate degrees of opioid toxicity when treatment with EGFR-I
resulted in sudden pain relief. In addition, after prolonged morphine use at a dose of >360 mg day−1, one patient experienced
grade one delirium upon rapid reduction in opiate use. The only
grade three AE observed, thought to be a very rare form of aseptic
meningitis, has been described previously.12 Four patients experienced greater pain reduction when anticonvulsants (pregabalin or
gabapentin) were reintroduced after treatment with EGFR-I was
terminated, than they had before EGFR-I use.
Discussion
experienced. Although pain flares were reduced in severity, the
more important aspect of pain relief, as indicated by the patients,
was reduction in the frequency and duration of the attacks.
Figure 2 shows the time to pain recurrence in patients who
stopped taking EGFR-I at some point during their follow-up.
The patients with malignant neuropathic pain continued to
receive EGFR-I until they were in the terminal stages of their diseases. In nine patients, EGFR-I was temporarily stopped, without
patients being aware of the pharmacokinetics of the drug in use.
Treatment of neuropathic pain with EGFR-I resulted in the majority of patients having clinically significant pain relief. Of particular
note was that pain relief was more rapid when EGFR-I was administered i.v. rather than orally, and onset of analgesia and recurrence of pain after stopping treatment were in accordance with
known pharmacokinetics of the different drugs. Furthermore all
four types of EGFR-I were effective, suggesting a class effect, and
reintroduction of EGFR-I after pain recurrence during treatment
interruptions was equally effective across all types. The positive
effects observed are further encouraged by the minimal adverse
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Case 10 (FBSS)
Erlotinib
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| Kersten et al.
Conclusion
Our observations that EGFR-I is effective in treating neuropathic
pain are of interest and are in keeping with the basic science work
to date suggesting their mechanism of action. We encourage reporting of other observations with EGFR-I which either support or
refute our findings. Clinical trials of EGFR-I in neuropathic pain
are now awaited with interest.
Authors’ contributions
Study design/planning: C.K., M.C., B.L., S.M.
Study conduct: C.K., M.C., S.M.
Data analysis: C.K., M.C., B.L., S.M.
Writing paper: C.K., M.C., B.L., S.M.
Revising paper: all authors.
Supplementary material
Supplementary material is available at British Journal of Anaesthesia
online.
Acknowledgements
The authors would like to acknowledge Dr. Renee Waage for her
dedication to her patients and to thank her for her important
contribution to this case series.
Declaration of interest
C.K., M.C. and S.M. have filed a US provisional patent application
for targeting the EGFR in neurological disorders.
Funding
The authors have received a grant from the South-Eastern Norway Regional Health Authority.
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The therapeutic effect of EGFR-I in neuropathic pain may be
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with chemotherapy-induced peripheral neuropathy and postherpetic neuralgia experienced only a gradual onset of pain relief,
reaching a maximum after one to two months. This is consistent
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and peripheral termini of peripheral nerves in these conditions
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