Chemotherapy-induced Peripheral Neuropathy
Conditions
Keywords
CIPN, Neuropathic pain, DLss, Peripheral neuropathy
Brief summary
The investigators propose that using the Diode Laser fiber type Selective Stimulator (DLss) in patients with chemotherapy-induced peripheral neuropathy (CIPN) will allow for the assessment of changes in small-fiber pain thresholds, to identify differences between subjects who received chemotherapy and developed painful CIPN, compared to subjects who received similar chemotherapy but did not develop painful CIPN (control group). Additionally, the investigators would like to investigate whether the response to DLss correlates with pain severity in patients with persistent painful neuropathy. The ultimate goal of this study is to develop a non-invasive, bedside quantitative test that is specific for painful CIPN. If the investigators' initial hypothesis is confirmed, the next step would be to design a prospective longitudinal study and assess changes in DLss early after initiation of chemotherapy, to determine whether this approach can help identify early predictive parameters of painful CIPN.
Detailed description
Painful chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy, occurring in more than 60% of patients at some point during the course of cancer treatment with commonly used drugs such as taxanes and platinum compounds. It potentially may result in severely diminished quality of life and dose reduction or/and treatment delay, which may ultimately impact survival. The mechanisms by which chemotherapy-induced nerve damage ultimately leads to pain are poorly understood, because virtually no structural or functional differences in nerve fibers between painless and painful peripheral neuropathy have been identified. As a result, there is no reliable way to predict which patients will develop persistent painful chemotherapy-induced peripheral neuropathy. The ultimate goal of this study is to develop a non-invasive, bedside quantitative test that is specific for painful CIPN. If our initial hypothesis is confirmed, the next step would be to design a prospective longitudinal study and assess changes in DLss early after initiation of chemotherapy, to determine whether this approach can help identify early predictive parameters of painful CIPN. In this other interventional study, we will test the utility of the Diode Laser fiber type Selective Stimulator (DLss) to identify sensory changes that are unique to patients with painful chemotherapy induced peripheral neuropathy (CIPN) vs. controls. Painful symptoms of CIPN develop in patients with differential nerve damage to Aδ vs C-type peripheral nerve fibers. We hypothesize that Aδ:C fiber threshold ratio, as measured by the DLss, will be different between patients with painful CIPN compared to control patients who received a similar regimen of chemotherapy, but did not develop painful CIPN. The confirmation of hypothesis may lead to a novel approach for early detection of CIPN. Subjects: 20 evaluable patients with painful CIPN following treatment with oxaliplatin, cisplatin, paclitaxel, docetaxel (or any combination of above) will be included in painful CIPN group, and 20 controls matched by the type of chemotherapy received, who did not develop painful CIPN. The study procedure will include a one-time visit for sensory assessments including: 1. Spontaneous pain at baseline on 0-10 Numerical Rating Scale (NRS); 2. Assessment of pain symptoms on Neuropathic pain Symptom Inventory (NPSI) and Brief Pain Inventory (BPI). 3. Assessment of mood on hospital anxiety and depression scale (HADS) 4. Quantitative sensory testing (QST): thermal detection and pain thresholds, mechanical detection threshold, temporal summation (TS), and conditioned pain modulation (CPM). The primary outcome is the comparison of Aδ:C fiber threshold ratio between patients who have developed painful CIPN, and the control subjects. In secondary analyses, we will generate Spearman correlation coefficient between the Aδ:C fiber threshold ratio and the severity of painful CIPN on NPSI scale.
Interventions
OTHERBrief Pain Inventory
-A self-administered questionnaire used to evaluate the severity of a patient's pain and the impact of this pain on the patient's daily functioning. The patient is asked to rate their worst, least, average, and current pain intensity (4 items which generate the PAIN SEVERITY score), list current treatments and their perceived effectiveness, and rate the degree that pain interferes with general activity, mood, walking ability, normal work, relations with other persons, sleep, and enjoyment of life (7 items which generate the PAIN INTERFERENCE score) on a 10 point scale.
OTHERHospital Anxiety and Depression Scale
* 14 item scale with even of the items relating to anxiety and seven relating to depression * Each item on the questionnaire is scored from 0-3 and this means that a patient can score between 0 and 21 for either anxiety or depression
-The NPSI questionnaire utilized in this study includes eight parameters (i.e., burning pain, squeezing pain, pressure pain, electric shock pain, stabbing pain, tingling pain, pins and needles pain and allodynia \[pain provoked by light touch\]). Each of the parameters includes recall of the past 24 hours
-Each patient will have an A and C fiber stimulation. Stimulation will be performed on the dorsum of the foot using stimulation previously published parameters to elicit burning pain, which is from activation of C-fibers and pinprick pain from A-fibers
PROCEDUREQuantitative sensory testing
* Quantitative sensory testing will be performed on the dorsal mid-foot and the ipsilateral shoulder will serve as control area * Cold and warm detection thresholds, cold and heat pain thresholds, mechanical detection thresholds, and wind-up ratio
PROCEDUREConditioned pain modulation efficiency
-Immersion of a hand up to the wrist to a thermostat-controlled water bath maintained at 12 degrees Celsius, and the application of a heat stimulus on the contralateral forearm.
OTHERSpontaneous pain at baseline on 0-10 Numerical Rating Scale (NRS)
-The subjects are asked to rate the intensity of their current pain on a 0-10 scale - 0 denoting no pain and 10 denoting worst imaginable pain.
Sponsors
National Institutes of Health (NIH)
Lasmed LLC
National Cancer Institute (NCI)
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Group A: Painful CIPN group * Age \>18 * Distal symmetric pain distribution (both feet, with or without pain in hands). * The pain appeared during or up to 12 weeks after treatment with oxaliplatin, cisplatin, paclitaxel, docetaxel or any combination of these. * Score of 4 or more on Douleur Neuropathique 4 (DN4) neuropathic pain questionnaire * Pain duration \> 2 months. * Patient report of average daily pain intensity in the last week ≥3 on 0-10 Numerical Rating Scale (NRS). * Able and willing to sign an Institutional Review Board (IRB)-approved written informed consent. Group B: Control group: * Age \>18 * History of cancer diagnosis, previously treated with at least 8 infusions of chemotherapy regimen that included oxaliplatin or at least 6 infusions of chemotherapy regimen that included cisplatin, paclitaxel, docetaxel, or any combination of these. * No ongoing pain in distal symmetric distribution (subjects with symptoms and signs such as mild numbness, or vibration sensation loss are eligible to be included in the control group). * Able and willing to sign an IRB-approved written informed consent. \* Subjects in the control group will be matched by the type of previous chemotherapy to the subjects in the Painful CIPN group. An additional attempt will be made to match controls by sex, age, cancer diagnosis, and cumulative neurotoxic chemotherapy dose.
Exclusion criteria
* History of pre-existing painful distal symmetric polyneuropathy prior to chemotherapy. * Alternative etiology exists for the distal painful symptoms. * Current or previous treatment with a vinca alkaloid (e.g. vincristine, vinblastine), bortezomib, or another agent which may cause major peripheral neurotoxicity. * Pregnant * Concomitant medication as follows: * Patients receiving chronic daily opioids, topical lidocaine or topical capsaicin will be excluded. * Patients receiving as needed (PRN) analgesics, including acetaminophen, NSAIDs or short-acting opioids, will be required not to take them 48h before testing, at for at least five half-lives of the specific analgesic, at the discretion of the investigators.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Aδ:C Fiber Detection Threshold Ratio | At the time of the DLss (day 1) | Comparison of the Aδ:C fiber detection threshold ratio (as measured by the DLss) between patients with painful neuropathy and patients who did not develop painful neuropathy following similar cancer chemotherapy |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Aδ:C Pain Threshold Ratio | At the time of the DLss (day 1) | Aδ:C pain threshold shows Aδ fiber threshold divided by C fiber threshold measured by DLss detection and pain threshold protocols. |
| The Severity of Neuropathy on NPSI Scale. | At the time of the DLss (day 1) | The severity of painful CIPN on Neuropathic Pain Symptom Inventory (NPSI) scale. Increased NPSI (0-100) score indicates more severe neuropathic pain. |
Countries
United States
Participant flow
Recruitment details
This study was conducted at Washington University in St Louis School of Medicine. Participants were recruited between September 17, 2018, and September 17, 2019.
Pre-assignment details
This is a case-control study. Case group: Patients with current symptoms of painful chemotherapy-induced peripheral neuropathy (CIPN) following treatment with oxaliplatin, cisplatin, paclitaxel, or docetaxel. Control group: patients who received the same chemotherapy agents, but who did not report current (or other long-term) painful CIPN.
Participants by arm
| Arm | Count |
|---|---|
| Group A: Painful CIPN Group Patients after chemotherapy with painful neuropathy | 20 |
| Group B: Control Group Patients after chemotherapy without painful neuropathy | 20 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | visit scheduling conflicts | 2 | 0 |
Baseline characteristics
| Characteristic | Group A: Painful CIPN Group | Group B: Control Group | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 6 Participants | 3 Participants | 9 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 17 Participants | 31 Participants |
| Age, Continuous | 58.1 years STANDARD_DEVIATION 10.6 | 50.5 years STANDARD_DEVIATION 14.5 | 54.3 years STANDARD_DEVIATION 13.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 20 Participants | 40 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 17 Participants | 19 Participants | 36 Participants |
| Region of Enrollment United States | 20 participants | 20 participants | 40 participants |
| Sex: Female, Male Female | 18 Participants | 19 Participants | 37 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 20 |
| other Total, other adverse events | 1 / 20 | 0 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 |
Outcome results
Primary
Aδ:C Fiber Detection Threshold Ratio
Comparison of the Aδ:C fiber detection threshold ratio (as measured by the DLss) between patients with painful neuropathy and patients who did not develop painful neuropathy following similar cancer chemotherapy
Time frame: At the time of the DLss (day 1)
Population: Enrolled patients from control and case groups who completed Aδ:C fiber detection threshold ratio testing by DLss
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: Painful Neuropathy Group | Aδ:C Fiber Detection Threshold Ratio | 2.04 ratio | Standard Deviation 0.74 |
| Group B: Control Group | Aδ:C Fiber Detection Threshold Ratio | 1.57 ratio | Standard Deviation 0.39 |
p-value: 0.05Regression, Logistic
Secondary
The Aδ:C Pain Threshold Ratio
Aδ:C pain threshold shows Aδ fiber threshold divided by C fiber threshold measured by DLss detection and pain threshold protocols.
Time frame: At the time of the DLss (day 1)
Population: Aδ:C threshold ratios were measured among patients from both groups. Only patients who finished DLss testing for pain threshold determination were included in analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: Painful Neuropathy Group | The Aδ:C Pain Threshold Ratio | 1.95 ratio | Standard Deviation 0.71 |
| Group B: Control Group | The Aδ:C Pain Threshold Ratio | 1.60 ratio | Standard Deviation 0.42 |
p-value: 0.7525Spearman's correlation coefficient
p-value: 0.1876Spearman's correlation coefficien
p-value: 0.61Spearman's correlation coefficient
p-value: 0.2914Spearman's correlation coefficient
Secondary
The Severity of Neuropathy on NPSI Scale.
The severity of painful CIPN on Neuropathic Pain Symptom Inventory (NPSI) scale. Increased NPSI (0-100) score indicates more severe neuropathic pain.
Time frame: At the time of the DLss (day 1)
Population: Only patients who completed NPSI questionnaire were included in analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: Painful Neuropathy Group | The Severity of Neuropathy on NPSI Scale. | 32.60 score on a scale | Standard Deviation 19.89 |
| Group B: Control Group | The Severity of Neuropathy on NPSI Scale. | 0.2 score on a scale | Standard Deviation 0.7 |