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Lise Ventzel, Caspar S Madsen, Páll Karlsson, Hatice Tankisi, Baris Isak, Anders Fuglsang-Frederiksen, Anders B Jensen, Anni R Jensen, Troels S Jensen, Nanna B Finnerup, Chronic Pain and Neuropathy Following Adjuvant Chemotherapy, Pain Medicine, Volume 19, Issue 9, September 2018, Pages 1813–1824, https://doi.org/10.1093/pm/pnx231
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Abstract
To determine symptoms and characteristics of chronic sensory neuropathy in patients treated with oxaliplatin and docetaxel, including patterns of somatosensory abnormalities, pain descriptors, and psychological functioning.
A retrospective cross-sectional study.
A chronic pain research center.
Thirty-eight patients with chronic peripheral pain and/or dysesthesia following chemotherapy.
Sensory profiles, psychological functioning, and quality of life were assessed using standardized questionnaires. In addition, standardized quantitative sensory testing and nerve conduction studies were carried out.
The sensory profiles and clinical symptoms were very similar in the two groups. Pricking, numbness, and burning were common descriptors in both groups, and the predominant finding was sensory loss to A beta–mediated sensory modalities with decreased mechanical and vibration detection thresholds. A high frequency of abnormalities in thermal sensory limen and the presence of paradoxical heat sensation seem to be sensitive markers of small fiber loss. Both groups had mainly sensory, axonal large fiber or mixed fiber polyneuropathy, which tended to be most severe in the oxaliplatin group.
Both oxaliplatin-induced and docetaxel-induced polyneuropathies represent a significant problem that affects the daily life of the patients. Our results, defining the somatosensory phenotype, can improve the understanding of the pathophysiological mechanisms useful for future studies in the tailored treatment of prevention of chemotherapy-induced peripheral neuropathy and pain.
Introduction
Polyneuropathy and pain or dysesthesia are well-known complications following treatment with neurotoxic chemotherapy [1]. Docetaxel, which increases disease-free and overall survival in high-risk breast cancer patients [2], and oxaliplatin, which increases disease-free and overall survival in stage II or III colon cancer [3], are shown to be associated with neurotoxicity. The clinical presentation of sensory symptoms during treatment with chemotherapy differs between the two groups, with a high frequency of patients with cold allodynia in the oxaliplatin group, whereas this symptom is almost nonexisting in the docetaxel group [4]. Both therapies may cause a chronic, progressive, length-dependent, mainly sensory, axonal polyneuropathy [5].
Docetaxel-induced neuropathy is one of the most common nonhematological side effects of adjuvant chemotherapy for high-risk breast cancer [6]. Recent studies have shown that 15% (clinician-reported) and 34% (patient-reported) of patients receiving docetaxel developed grades 2–4 neuropathy using the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE v. 3) [7]. The mechanisms behind docetaxel-induced neuropathy include interference with microtubule-based axonal transport and macrophage activation in both the dorsal root ganglion (DRG) and peripheral nerves [8].
Neuropathy due to oxaliplatin can be divided into an acute and a chronic form. Acute neurotoxicity is seen in almost all patients and consists of cold-induced dysesthesia, particularly of the hands and throat [9]. The symptoms occur during or within hours after the treatment and are usually reversible over the following hours or days [10]. Chronic oxaliplatin-induced polyneuropathy is associated with cumulative dose [11,12] and is dominated by numbness/tingling in the distal extremities, with the most severe symptoms in the feet [13,14]. It is suggested that acute oxaliplatin-induced neuropathy is caused by modulation of axonal voltage-gated sodium channels. The chronic form is considered to be induced by functional changes in the DRG cells [8]. Depending on the method of evaluation, chronic oxaliplatin-induced neuropathy was reported in 28% [15], 29% [16], and 10% [17] of the patients.
Chronic polyneuropathy is known to affect patients’ quality of life [16], and since an increasing number of cancer patients survive or live longer with their cancer, it is relevant to look at the long-term side effects and their impact on the patients’ quality of life and function. Dysesthesia, pain, somatosensory signs, and psychological functioning are well characterized in patients with, for example, HIV-associated neuropathy and mixed polyneuropathy [18,19], and in patients with acute oxaliplatin-induced neuropathy [20,21]; however, previous studies on chronic neuropathy due to oxaliplatin and docetaxel have mainly used questionnaires and clinician-reported CTCAEs, and our knowledge of sensory symptoms and profiles in the chronic stages is thus limited [22,23]. It has been suggested that pain has a significant effect on psychological functioning [4] although it is also possible that persistent anxiety and depressive symptoms increase the reporting of pain. Comparing chronic neuropathy and pain in two groups of patients should therefore include psychological functioning.
In this study, we aimed to examine and compare the patterns of somatosensory abnormalities, pain descriptors, and psychological functioning in two groups of patients with chronic chemotherapy-induced neuropathy induced by two different types of chemotherapy, which has been shown to have different presentations in the acute phase and is used in two different populations.
Methods
Patients
The study was conducted at the Danish Pain Research Center and the Department of Clinical Neurophysiology, Aarhus University Hospital, Denmark, between April 2012 and February 2013. Approval was given by the Central Denmark Region Committees on Health Research Ethics (no. M-20110158) and the Danish Data Protection Agency (no. 2011–41-5725), and all participants signed an informed consent document at inclusion. Inclusion criteria were age above 17 years, treatment with standard adjuvant capecetabin and oxaliplatin (Xelox) for high-risk colorectal cancer or standard docetaxel for high-risk breast cancer more than six months ago, completion of at least one cycle of oxaliplatin or docetaxel during chemotherapy treatment and spontaneous or evoked pain and/or dysesthesia bilaterally in the hands and/or feet with an intensity above 3 on a numeric rating scale (NRS; 0–10). Exclusion criteria were inability to speak, read, and understand Danish, known metastatic cancer, previous treatment with chemotherapy, neuropathy from a cause other than chemotherapy, neurological or psychiatric disorders, diabetes, significant medical conditions, alcohol abuse, other chronic pain with an intensity above 5 on the NRS that could not be distinguished from chemotherapy-induced pain, spinal stenosis, and vascular disease (Fontaine grade II or higher). Patients were recruited from the Department of Oncology, Aarhus University Hospital, Denmark. Information about the number of cycles and dosage of chemotherapy was collected from their medical charts. A group of 15 age- and gender-matched healthy participants were included as controls to determine intra-epidermal nerve fiber density (IENFD) from skin biopsies. The exclusion criteria were the same as for the patients.
Questionnaires
Quality of life was assessed using the EuroQol 5 dimension (EQ-5 D) self-report questionnaire (EuroQol Group 1995). Anxiety and depression were rated using the Hospital Anxiety and Depression Scale (HADS) [24]. Pain interference was assessed using the Brief Inventory Pain (BPI) [25]. For assessing chemotherapy-induced neuropathy, a specific questionnaire divided into three parts addressing, respectively, the upper extremity, the lower extremity, and the orofacial area was used. Patients were asked if they had specific symptoms (“yes” or “no”). The questionnaire contains questions about dysesthesia (e.g., burning pain with or without cold), a greater than normal sense of touch, and paresthesia (e.g., tingling, numbness, and difficulty feeling things) [13]. We used the painDETECT questionnaire to further characterize the patients’ pain descriptors [26]. Patients were also asked to complete the Pain Catastrophizing Scale (PCS) [27].
Quantitative Sensory Testing
In all patients, the dorsum of the hand and the foot on the same side of the body were investigated using the quantitative sensory testing (QST) protocol of the German Research Network on Neuropathic Pain (DFNS) [28]. The side of investigation was randomized. Breast cancer surgery patients were, however, examined on the side contralateral to the surgery. The clinical examination was performed by the same investigators (LV and CSM) in all patients. The QST protocol includes standardized equipment and verbal instructions as well as a standardized QST battery with 13 different noninvasive thermal and mechanical tests of large and small fiber function.
Skin Biopsies
Skin biopsies were taken 5–8 cm above the ankle and 5 cm above the wrist using a disposable 3-mm punch (Miltex, York, PA, USA). Immediately after the procedure, the biopsies were fixed in 2% paraformaldehyde-lysine-periodate for 18–24 hours, followed by an overnight cryoprotection in 20% glycerol and 0.08 M Sorenson’s PO4 buffer. Biopsies were stored in a –80 °C freezer until staining; 50-µm thick cryostat sections were cut vertically in relation to the epidermis direction (Microm Cryostat HM 500 OM, Zeiss, Germany). Three random sections were immunostained using anti-PGP 9.5 antibody (1:10.000, AbD Serotec, Dusseldorf, Germany) to visualize the nerve fibers, and IENFD was determined as described in details elsewhere. All sections were counted by the same investigator (PK), who was blinded to the origin of the biopsies.
Nerve Conduction Studies
All electrophysiological evaluations were done with Keypoint EMG equipment (Medtronic, Skovlunde, Denmark) and conventional surface electrode techniques. The results were compared with the laboratory control database. Antidromic sensory nerve conduction studies (NCSs) were performed on the median nerve to digits II and III unilaterally and on the sural nerve bilaterally. In addition, NCSs were performed on the antidromic dorsal sural and orthodromic medial plantar nerves to evaluate the distal sensory nerve segments in lower extremities, as previously described [29]. Conduction velocities and amplitudes were the evaluated parameters. Base to peak amplitude was used for the median nerve, and peak to peak for the other sensory nerves. Motor NCSs were performed on the median nerve unilaterally and the peroneal and tibial nerves bilaterally using conventional methods. Distal motor latencies, conduction velocities, peak-to-peak amplitudes, and minimum F-wave latencies were evaluated in all motor NCSs. A diagnosis of large fiber polyneuropathy required at least two abnormal sensory nerves or motor nerves [30]. The criteria proposed by the European Standardised Telematic Tool to Evaluate Electrodiagnostic Methods group were used for the classification as axonal, demyelinating, mixed, or unclassified neuropathy.
Statistical Analysis
Stata/IC version 12.1 was used for statistical analysis. Normality was checked using histograms and QQ plots. Numerical data were analyzed depending on the distribution using unpaired t test (normal distribution) or Wilcoxon rank-sum (Mann–Whitney) test (non-normal distribution). The results are expressed as mean values ± SD. Categorical data were analyzed using Fisher’s exact test. P values of less than 0.05 were considered statistically significant. Paradoxical heat sensation, cold pain thresholds, heat pain thresholds, and vibration detection thresholds were normally distributed. The other QST parameters were normally distributed in log-space and therefore transformed logarithmically before calculating mean and standard deviation [28].
Results
Patients and Pain Characteristics
Table 1 presents the demographic and clinical data of 38 patients (20 in the docetaxel group and 18 ind the oxaliplatin group), including self-reported pain and dysesthesia and the most common symptoms of neuropathy according to the specific questionnaire on chemotherapy-induced polyneuropathy. No patients reported motor symptoms. According to the PainDETECT questionnaire (Figure 1), the most common neuropathic pain symptoms were pricking, numbness, and burning in both groups.
. | Oxaliplatin (N = 20) . | Docetaxel (N = 18) . | P . |
---|---|---|---|
Females, No. (%) | 9 (45) | 18 (100) | <0.001* |
Age, mean (SD), y | 66.5 (5.9) | 56.0 (8.4) | <0.001* |
Height, mean (SD), cm | 174.7 (8.4) | 166.6 (6.8) | <0.001* |
Weight, mean (SD), kg | 82.8 (9.2) | 72.9 (14.3) | 0.02* |
Most common comorbidities | |||
Hypertension, No. (%) | 9 (45) | 4 (22) | 0.18 |
Hypercholesterolemia, No. (%) | 4 (20) | 3 (17) | 1.00 |
Other comorbidities†, No. (%) | 5 (25) | 4 (22) | 1.00 |
Most common medications | |||
Vitamins, incl. calcium and vitamin D, No. (%) | 6 (30) | 8 (44) | 0.5 |
Antihypertensive drugs, No. (%) | 8 (40) | 3 (17) | 0.2 |
Other medications‡ | |||
Cumulative dose, mean (SD), mg/m2 | 627 (124) | 301 (76) | |
Time since treatment, mean (SD), mo | 20 (4.7) | 31 (14.6) | 0.02* |
Patients reduced in dose, No. (%) | 18 (90) | 8 (44) | <0.001* |
Due to neuropathy, No. (%) | 17 (85) | 5 (28) | <0.001* |
For other reasons, No. (%) | 1 (5) | 3 (17) | 0.08 |
Patients with pain, No. (%) | 5 (25) | 10 (56) | 0.10 |
Hands, No. (%) | 2 (10) | 2 (11) | 1.00 |
Feet, No. (%) | 4 (20) | 8 (44) | 0.16 |
Patients with unpleasantness, No. (%) | 20 (100) | 18 (100) | 1.00 |
Hands, No. (%) | 18 (90) | 13 (72) | 0.22 |
Feet, No. (%) | 20 (100) | 18 (100) | 1.00 |
Intensity of unpleasantness (NRS) | |||
Hands, mean (SD) | 4.1 (2.8) | 2.8 (2.3) | 0.33 |
Feet, mean (SD) | 6.2 (1.9) | 6.0 (2.7) | 0.73 |
Most common symptoms in upper extremity§ | |||
Tingling or pins and needles, No. (%) | 15 (75) | 13 (72) | 1.00 |
Numbness, No. (%) | 9 (45) | 8 (44) | 1.00 |
Burning pain or discomfort with cold, No. (%) | 6 (30) | 4 (22) | 0.72 |
A greater than normal sense of touch, No. (%) | 4 (20) | 5 (28) | 0.71 |
Most common symptoms in lower extremity† | |||
Tingling (pins and needles), No. (%) | 19 (95) | 17 (94) | 1.00 |
Numbness, No. (%) | 13 (65) | 8 (44) | 0.33 |
Legs feeling heavy, No. (%) | 11 (55) | 10 (56) | 1.00 |
Burning pain or discomfort with cold, No. (%) | 11 (55) | 6 (33) | 0.21 |
Burning pain or discomfort without cold, No. (%) | 7 (35) | 9 (50) | 0.51 |
A greater than normal sense of touch, No. (%) | 6 (30) | 8 (44) | 0.50 |
. | Oxaliplatin (N = 20) . | Docetaxel (N = 18) . | P . |
---|---|---|---|
Females, No. (%) | 9 (45) | 18 (100) | <0.001* |
Age, mean (SD), y | 66.5 (5.9) | 56.0 (8.4) | <0.001* |
Height, mean (SD), cm | 174.7 (8.4) | 166.6 (6.8) | <0.001* |
Weight, mean (SD), kg | 82.8 (9.2) | 72.9 (14.3) | 0.02* |
Most common comorbidities | |||
Hypertension, No. (%) | 9 (45) | 4 (22) | 0.18 |
Hypercholesterolemia, No. (%) | 4 (20) | 3 (17) | 1.00 |
Other comorbidities†, No. (%) | 5 (25) | 4 (22) | 1.00 |
Most common medications | |||
Vitamins, incl. calcium and vitamin D, No. (%) | 6 (30) | 8 (44) | 0.5 |
Antihypertensive drugs, No. (%) | 8 (40) | 3 (17) | 0.2 |
Other medications‡ | |||
Cumulative dose, mean (SD), mg/m2 | 627 (124) | 301 (76) | |
Time since treatment, mean (SD), mo | 20 (4.7) | 31 (14.6) | 0.02* |
Patients reduced in dose, No. (%) | 18 (90) | 8 (44) | <0.001* |
Due to neuropathy, No. (%) | 17 (85) | 5 (28) | <0.001* |
For other reasons, No. (%) | 1 (5) | 3 (17) | 0.08 |
Patients with pain, No. (%) | 5 (25) | 10 (56) | 0.10 |
Hands, No. (%) | 2 (10) | 2 (11) | 1.00 |
Feet, No. (%) | 4 (20) | 8 (44) | 0.16 |
Patients with unpleasantness, No. (%) | 20 (100) | 18 (100) | 1.00 |
Hands, No. (%) | 18 (90) | 13 (72) | 0.22 |
Feet, No. (%) | 20 (100) | 18 (100) | 1.00 |
Intensity of unpleasantness (NRS) | |||
Hands, mean (SD) | 4.1 (2.8) | 2.8 (2.3) | 0.33 |
Feet, mean (SD) | 6.2 (1.9) | 6.0 (2.7) | 0.73 |
Most common symptoms in upper extremity§ | |||
Tingling or pins and needles, No. (%) | 15 (75) | 13 (72) | 1.00 |
Numbness, No. (%) | 9 (45) | 8 (44) | 1.00 |
Burning pain or discomfort with cold, No. (%) | 6 (30) | 4 (22) | 0.72 |
A greater than normal sense of touch, No. (%) | 4 (20) | 5 (28) | 0.71 |
Most common symptoms in lower extremity† | |||
Tingling (pins and needles), No. (%) | 19 (95) | 17 (94) | 1.00 |
Numbness, No. (%) | 13 (65) | 8 (44) | 0.33 |
Legs feeling heavy, No. (%) | 11 (55) | 10 (56) | 1.00 |
Burning pain or discomfort with cold, No. (%) | 11 (55) | 6 (33) | 0.21 |
Burning pain or discomfort without cold, No. (%) | 7 (35) | 9 (50) | 0.51 |
A greater than normal sense of touch, No. (%) | 6 (30) | 8 (44) | 0.50 |
P < 0.05.
Osteoarthritis, osteoporosis, and benign prostatic hypertrophy.
Statins, NSAID, and Tamsulosin.
Specific chemotherapy-induced neuropathy questionnaire [13] .
. | Oxaliplatin (N = 20) . | Docetaxel (N = 18) . | P . |
---|---|---|---|
Females, No. (%) | 9 (45) | 18 (100) | <0.001* |
Age, mean (SD), y | 66.5 (5.9) | 56.0 (8.4) | <0.001* |
Height, mean (SD), cm | 174.7 (8.4) | 166.6 (6.8) | <0.001* |
Weight, mean (SD), kg | 82.8 (9.2) | 72.9 (14.3) | 0.02* |
Most common comorbidities | |||
Hypertension, No. (%) | 9 (45) | 4 (22) | 0.18 |
Hypercholesterolemia, No. (%) | 4 (20) | 3 (17) | 1.00 |
Other comorbidities†, No. (%) | 5 (25) | 4 (22) | 1.00 |
Most common medications | |||
Vitamins, incl. calcium and vitamin D, No. (%) | 6 (30) | 8 (44) | 0.5 |
Antihypertensive drugs, No. (%) | 8 (40) | 3 (17) | 0.2 |
Other medications‡ | |||
Cumulative dose, mean (SD), mg/m2 | 627 (124) | 301 (76) | |
Time since treatment, mean (SD), mo | 20 (4.7) | 31 (14.6) | 0.02* |
Patients reduced in dose, No. (%) | 18 (90) | 8 (44) | <0.001* |
Due to neuropathy, No. (%) | 17 (85) | 5 (28) | <0.001* |
For other reasons, No. (%) | 1 (5) | 3 (17) | 0.08 |
Patients with pain, No. (%) | 5 (25) | 10 (56) | 0.10 |
Hands, No. (%) | 2 (10) | 2 (11) | 1.00 |
Feet, No. (%) | 4 (20) | 8 (44) | 0.16 |
Patients with unpleasantness, No. (%) | 20 (100) | 18 (100) | 1.00 |
Hands, No. (%) | 18 (90) | 13 (72) | 0.22 |
Feet, No. (%) | 20 (100) | 18 (100) | 1.00 |
Intensity of unpleasantness (NRS) | |||
Hands, mean (SD) | 4.1 (2.8) | 2.8 (2.3) | 0.33 |
Feet, mean (SD) | 6.2 (1.9) | 6.0 (2.7) | 0.73 |
Most common symptoms in upper extremity§ | |||
Tingling or pins and needles, No. (%) | 15 (75) | 13 (72) | 1.00 |
Numbness, No. (%) | 9 (45) | 8 (44) | 1.00 |
Burning pain or discomfort with cold, No. (%) | 6 (30) | 4 (22) | 0.72 |
A greater than normal sense of touch, No. (%) | 4 (20) | 5 (28) | 0.71 |
Most common symptoms in lower extremity† | |||
Tingling (pins and needles), No. (%) | 19 (95) | 17 (94) | 1.00 |
Numbness, No. (%) | 13 (65) | 8 (44) | 0.33 |
Legs feeling heavy, No. (%) | 11 (55) | 10 (56) | 1.00 |
Burning pain or discomfort with cold, No. (%) | 11 (55) | 6 (33) | 0.21 |
Burning pain or discomfort without cold, No. (%) | 7 (35) | 9 (50) | 0.51 |
A greater than normal sense of touch, No. (%) | 6 (30) | 8 (44) | 0.50 |
. | Oxaliplatin (N = 20) . | Docetaxel (N = 18) . | P . |
---|---|---|---|
Females, No. (%) | 9 (45) | 18 (100) | <0.001* |
Age, mean (SD), y | 66.5 (5.9) | 56.0 (8.4) | <0.001* |
Height, mean (SD), cm | 174.7 (8.4) | 166.6 (6.8) | <0.001* |
Weight, mean (SD), kg | 82.8 (9.2) | 72.9 (14.3) | 0.02* |
Most common comorbidities | |||
Hypertension, No. (%) | 9 (45) | 4 (22) | 0.18 |
Hypercholesterolemia, No. (%) | 4 (20) | 3 (17) | 1.00 |
Other comorbidities†, No. (%) | 5 (25) | 4 (22) | 1.00 |
Most common medications | |||
Vitamins, incl. calcium and vitamin D, No. (%) | 6 (30) | 8 (44) | 0.5 |
Antihypertensive drugs, No. (%) | 8 (40) | 3 (17) | 0.2 |
Other medications‡ | |||
Cumulative dose, mean (SD), mg/m2 | 627 (124) | 301 (76) | |
Time since treatment, mean (SD), mo | 20 (4.7) | 31 (14.6) | 0.02* |
Patients reduced in dose, No. (%) | 18 (90) | 8 (44) | <0.001* |
Due to neuropathy, No. (%) | 17 (85) | 5 (28) | <0.001* |
For other reasons, No. (%) | 1 (5) | 3 (17) | 0.08 |
Patients with pain, No. (%) | 5 (25) | 10 (56) | 0.10 |
Hands, No. (%) | 2 (10) | 2 (11) | 1.00 |
Feet, No. (%) | 4 (20) | 8 (44) | 0.16 |
Patients with unpleasantness, No. (%) | 20 (100) | 18 (100) | 1.00 |
Hands, No. (%) | 18 (90) | 13 (72) | 0.22 |
Feet, No. (%) | 20 (100) | 18 (100) | 1.00 |
Intensity of unpleasantness (NRS) | |||
Hands, mean (SD) | 4.1 (2.8) | 2.8 (2.3) | 0.33 |
Feet, mean (SD) | 6.2 (1.9) | 6.0 (2.7) | 0.73 |
Most common symptoms in upper extremity§ | |||
Tingling or pins and needles, No. (%) | 15 (75) | 13 (72) | 1.00 |
Numbness, No. (%) | 9 (45) | 8 (44) | 1.00 |
Burning pain or discomfort with cold, No. (%) | 6 (30) | 4 (22) | 0.72 |
A greater than normal sense of touch, No. (%) | 4 (20) | 5 (28) | 0.71 |
Most common symptoms in lower extremity† | |||
Tingling (pins and needles), No. (%) | 19 (95) | 17 (94) | 1.00 |
Numbness, No. (%) | 13 (65) | 8 (44) | 0.33 |
Legs feeling heavy, No. (%) | 11 (55) | 10 (56) | 1.00 |
Burning pain or discomfort with cold, No. (%) | 11 (55) | 6 (33) | 0.21 |
Burning pain or discomfort without cold, No. (%) | 7 (35) | 9 (50) | 0.51 |
A greater than normal sense of touch, No. (%) | 6 (30) | 8 (44) | 0.50 |
P < 0.05.
Osteoarthritis, osteoporosis, and benign prostatic hypertrophy.
Statins, NSAID, and Tamsulosin.
Specific chemotherapy-induced neuropathy questionnaire [13] .
Psychological Function and Quality of Life
Patients treated with docetaxel had significantly higher anxiety (P = 0.02) and depression (P = 0.04) scores than patients treated with oxaliplatin measured by the HADS (Table 2). Looking at the female patients only, there was still a significant difference in anxiety score (P = 0.01), but no difference in depression score (P = 0.11).
. | Oxaliplatin (N = 20) . | Docetaxel (N = 18) . | P . |
---|---|---|---|
HADS | |||
Depression score, mean (SD) | 0.8 (0.9) | 2.4 (2.6) | 0.04* |
No. with depression (%)† | 0 (0) | 1 (0.06) | 0.47 |
Anxiety score, mean (SD) | 2.7 (2.8) | 5.6 (3.6) | 0.02* |
No. with anxiety (%)‡ | 2 (10) | 7 (39) | 0.06 |
PCS | |||
Rumination, mean (SD) | 3.4 (3.1) | 6 (4.0) | 0.03* |
Magnification, mean (SD) | 1.5 (1.5) | 2.2 (1.7) | 0.17 |
Helplessness, mean (SD) | 3.2 (2.9) | 6.5 (4.3) | 0.01* |
Total, mean (SD) | 8 (6.2) | 14.7 (8.9) | 0.01* |
EQ-5D | |||
Motility, No. (%)§ | 4 (20) | 4 (22) | 1.00 |
Self-care, No. (%)§ | 1 (5) | 5 (5.6) | 1.00 |
Usual activities, No. (%)§ | 7 (35) | 9 (50) | 0.51 |
Pain/discomfort, No. (%)§ | 15 (75) | 15 (83) | 0.70 |
Anxiety/depression, No. (%)§ | 3 (15) | 7 (39) | 0.14 |
EQ-5D VAS, mean (SD) | 83.7 (9.5) | 79.7 (17.6) | 0.91 |
BPI | |||
General activity, mean (SD) | 3.1 (2.3) | 2.3 (2.6) | 0.21 |
Mood, mean (SD) | 1.1 (1.2) | 1.7 (2.3) | 0.77 |
Walking, mean (SD) | 2.7 (2.4) | 2.3 (2.4) | 0.62 |
Normal work, mean (SD) | 1.8 (2.1) | 2.2 (2.7) | 0.75 |
Relationships, mean (SD) | 0.5 (0.7) | 1.2 (2.2) | 0.78 |
Sleep, mean (SD) | 0.8 (1.3) | 2.1 (2.7) | 0.09 |
Enjoyment of life, mean (SD) | 1.1 (1.5) | 1.4 (2.2) | 0.93 |
Total, mean (SD) | 10.9 (8.0) | 13.2 (15.2) | 0.69 |
. | Oxaliplatin (N = 20) . | Docetaxel (N = 18) . | P . |
---|---|---|---|
HADS | |||
Depression score, mean (SD) | 0.8 (0.9) | 2.4 (2.6) | 0.04* |
No. with depression (%)† | 0 (0) | 1 (0.06) | 0.47 |
Anxiety score, mean (SD) | 2.7 (2.8) | 5.6 (3.6) | 0.02* |
No. with anxiety (%)‡ | 2 (10) | 7 (39) | 0.06 |
PCS | |||
Rumination, mean (SD) | 3.4 (3.1) | 6 (4.0) | 0.03* |
Magnification, mean (SD) | 1.5 (1.5) | 2.2 (1.7) | 0.17 |
Helplessness, mean (SD) | 3.2 (2.9) | 6.5 (4.3) | 0.01* |
Total, mean (SD) | 8 (6.2) | 14.7 (8.9) | 0.01* |
EQ-5D | |||
Motility, No. (%)§ | 4 (20) | 4 (22) | 1.00 |
Self-care, No. (%)§ | 1 (5) | 5 (5.6) | 1.00 |
Usual activities, No. (%)§ | 7 (35) | 9 (50) | 0.51 |
Pain/discomfort, No. (%)§ | 15 (75) | 15 (83) | 0.70 |
Anxiety/depression, No. (%)§ | 3 (15) | 7 (39) | 0.14 |
EQ-5D VAS, mean (SD) | 83.7 (9.5) | 79.7 (17.6) | 0.91 |
BPI | |||
General activity, mean (SD) | 3.1 (2.3) | 2.3 (2.6) | 0.21 |
Mood, mean (SD) | 1.1 (1.2) | 1.7 (2.3) | 0.77 |
Walking, mean (SD) | 2.7 (2.4) | 2.3 (2.4) | 0.62 |
Normal work, mean (SD) | 1.8 (2.1) | 2.2 (2.7) | 0.75 |
Relationships, mean (SD) | 0.5 (0.7) | 1.2 (2.2) | 0.78 |
Sleep, mean (SD) | 0.8 (1.3) | 2.1 (2.7) | 0.09 |
Enjoyment of life, mean (SD) | 1.1 (1.5) | 1.4 (2.2) | 0.93 |
Total, mean (SD) | 10.9 (8.0) | 13.2 (15.2) | 0.69 |
BPI = Brief Pain Inventory; EQ-5 D = health questionnaire; HADS = Hospital Anxiety and Depression Scale; PCS = Pain Catastrophizing Scale.
P < 0.05.
Depression score > 7.
Anxiety score > 7.
Number (%) of patients who reported some or serious problems.
. | Oxaliplatin (N = 20) . | Docetaxel (N = 18) . | P . |
---|---|---|---|
HADS | |||
Depression score, mean (SD) | 0.8 (0.9) | 2.4 (2.6) | 0.04* |
No. with depression (%)† | 0 (0) | 1 (0.06) | 0.47 |
Anxiety score, mean (SD) | 2.7 (2.8) | 5.6 (3.6) | 0.02* |
No. with anxiety (%)‡ | 2 (10) | 7 (39) | 0.06 |
PCS | |||
Rumination, mean (SD) | 3.4 (3.1) | 6 (4.0) | 0.03* |
Magnification, mean (SD) | 1.5 (1.5) | 2.2 (1.7) | 0.17 |
Helplessness, mean (SD) | 3.2 (2.9) | 6.5 (4.3) | 0.01* |
Total, mean (SD) | 8 (6.2) | 14.7 (8.9) | 0.01* |
EQ-5D | |||
Motility, No. (%)§ | 4 (20) | 4 (22) | 1.00 |
Self-care, No. (%)§ | 1 (5) | 5 (5.6) | 1.00 |
Usual activities, No. (%)§ | 7 (35) | 9 (50) | 0.51 |
Pain/discomfort, No. (%)§ | 15 (75) | 15 (83) | 0.70 |
Anxiety/depression, No. (%)§ | 3 (15) | 7 (39) | 0.14 |
EQ-5D VAS, mean (SD) | 83.7 (9.5) | 79.7 (17.6) | 0.91 |
BPI | |||
General activity, mean (SD) | 3.1 (2.3) | 2.3 (2.6) | 0.21 |
Mood, mean (SD) | 1.1 (1.2) | 1.7 (2.3) | 0.77 |
Walking, mean (SD) | 2.7 (2.4) | 2.3 (2.4) | 0.62 |
Normal work, mean (SD) | 1.8 (2.1) | 2.2 (2.7) | 0.75 |
Relationships, mean (SD) | 0.5 (0.7) | 1.2 (2.2) | 0.78 |
Sleep, mean (SD) | 0.8 (1.3) | 2.1 (2.7) | 0.09 |
Enjoyment of life, mean (SD) | 1.1 (1.5) | 1.4 (2.2) | 0.93 |
Total, mean (SD) | 10.9 (8.0) | 13.2 (15.2) | 0.69 |
. | Oxaliplatin (N = 20) . | Docetaxel (N = 18) . | P . |
---|---|---|---|
HADS | |||
Depression score, mean (SD) | 0.8 (0.9) | 2.4 (2.6) | 0.04* |
No. with depression (%)† | 0 (0) | 1 (0.06) | 0.47 |
Anxiety score, mean (SD) | 2.7 (2.8) | 5.6 (3.6) | 0.02* |
No. with anxiety (%)‡ | 2 (10) | 7 (39) | 0.06 |
PCS | |||
Rumination, mean (SD) | 3.4 (3.1) | 6 (4.0) | 0.03* |
Magnification, mean (SD) | 1.5 (1.5) | 2.2 (1.7) | 0.17 |
Helplessness, mean (SD) | 3.2 (2.9) | 6.5 (4.3) | 0.01* |
Total, mean (SD) | 8 (6.2) | 14.7 (8.9) | 0.01* |
EQ-5D | |||
Motility, No. (%)§ | 4 (20) | 4 (22) | 1.00 |
Self-care, No. (%)§ | 1 (5) | 5 (5.6) | 1.00 |
Usual activities, No. (%)§ | 7 (35) | 9 (50) | 0.51 |
Pain/discomfort, No. (%)§ | 15 (75) | 15 (83) | 0.70 |
Anxiety/depression, No. (%)§ | 3 (15) | 7 (39) | 0.14 |
EQ-5D VAS, mean (SD) | 83.7 (9.5) | 79.7 (17.6) | 0.91 |
BPI | |||
General activity, mean (SD) | 3.1 (2.3) | 2.3 (2.6) | 0.21 |
Mood, mean (SD) | 1.1 (1.2) | 1.7 (2.3) | 0.77 |
Walking, mean (SD) | 2.7 (2.4) | 2.3 (2.4) | 0.62 |
Normal work, mean (SD) | 1.8 (2.1) | 2.2 (2.7) | 0.75 |
Relationships, mean (SD) | 0.5 (0.7) | 1.2 (2.2) | 0.78 |
Sleep, mean (SD) | 0.8 (1.3) | 2.1 (2.7) | 0.09 |
Enjoyment of life, mean (SD) | 1.1 (1.5) | 1.4 (2.2) | 0.93 |
Total, mean (SD) | 10.9 (8.0) | 13.2 (15.2) | 0.69 |
BPI = Brief Pain Inventory; EQ-5 D = health questionnaire; HADS = Hospital Anxiety and Depression Scale; PCS = Pain Catastrophizing Scale.
P < 0.05.
Depression score > 7.
Anxiety score > 7.
Number (%) of patients who reported some or serious problems.
There was a difference between the groups for pain catastrophizing (Table 2). There was no difference in magnification, but patients in the docetaxel group scored higher on both rumination and helplessness. Excluding the male patients, we still found a significant difference between the groups for helplessness (P = 0.04).
No difference was seen between the two groups on any of the five dimensions of the EQ-5 D (Table 2). The most common complaint was pain/discomfort. There was no difference between the two groups in patient-rated health state, and for pain interference of the BPI there was no significant difference in the seven domains between the two groups (Table 2).
Quantitative Sensory Testing
The QST data are presented in Supplementary Table 1. Mean z-scores and standard deviation are shown for the hands (Figure 2A) and feet (Figure 2B).
In the upper extremity, the patients treated with oxaliplatin had lower values (more loss) for cold detection threshold (CDT), warm detection threshold (WDT), and pressure pain threshold (PPT) than patients treated with docetaxel, but only vibration detection threshold (VDT) fell outside the DFNS normative range (Figure 2A).
In the lower extremity (Figure 2B), mean z-scores were also predominantly within the normative range. Mechanical detection threshold (MDT) and VDT values in the oxaliplatin group were below the normative range, and group comparisons showed significant differences on PPT and MDT parameters, with more loss in the oxaliplatin-treated patients. Although the mean z-scores were predominantly within the normative range, individual patients fell outside the range. The frequency of abnormal QST values in each group is shown in Figure 3 and Supplementary Table 2. The main abnormal parameter was loss of sensory function. The most frequent abnormalities were increased MDT and VDT, as well as paradoxical heat sensation (PHS) in the feet and increased VDT in the hands. Thermal sensory limen (TSL) was more often abnormal than CDT and WDT. There was no group difference except that more patients in the oxaliplatin group had abnormal MDT in the lower extremity.
To display combinations of sensory abnormalities, a previously described [19] coding system was used. The sensory patterns of loss and gain in chemotherapy-induced polyneuropathy are summarized in Table 3. Collectively, the most frequent combination in the lower extremity was loss of at least one mechanical QST parameter (Gain0Loss2). Combinations with sensory gain were more common in the upper extremity, with 23.7% of patients presenting thermal gain in combination with sensory loss. However, the majority involved sensory loss.
A Dorsal Hand . | Gain 0(None)No. (%) . | Gain 1 (Thermal)No. (%) . | Gain 2 (Mechanical)No. (%) . | Gain 3(Both)No. (%) . | All No. (%) . |
---|---|---|---|---|---|
Loss 0 (none) | 6 (15.8) | 0 | 1 (2.6) | 3 (7.9) | 10 (26.3) |
Loss 1 (thermal) | 1 (2.6) | 0 | 0 | 0 | 1 (2.6) |
Loss 2 mechanical) | 8 (21.1) | 7 (18.4) | 4 (10.5) | 1 (2.6) | 20 (52.6) |
Loss 3 (both) | 5 (13.2) | 2 (5.3) | 0 | 0 | 7 (18.4) |
All | 20 (52.6) | 9 (23.7) | 5 (13.2) | 4 (10.5) | 38 (100) |
B Dorsal Foot | Gain 0(None) | Gain 1 (Thermal) | Gain 2 (Mechanical) | Gain 3(Both) | All |
Loss 0 (none) | 3 (7.9) | 0 | 6 (15.8) | 1 (2.6) | 10 (26.3) |
Loss 1 (thermal) | 2 (5.3) | 0 | 0 | 0 | 2 (5.3) |
Loss 2 mechanical) | 14 (36.8) | 1 (2.6) | 5 (13.2) | 0 | 20 (52.6) |
Loss 3 (both) | 5 (13.2) | 0 | 1 (2.6) | 0 | 6 (15.8) |
All | 24 (63.2) | 1 (2.6) | 12 (31.6) | 1 (2.6) | 38 (100) |
A Dorsal Hand . | Gain 0(None)No. (%) . | Gain 1 (Thermal)No. (%) . | Gain 2 (Mechanical)No. (%) . | Gain 3(Both)No. (%) . | All No. (%) . |
---|---|---|---|---|---|
Loss 0 (none) | 6 (15.8) | 0 | 1 (2.6) | 3 (7.9) | 10 (26.3) |
Loss 1 (thermal) | 1 (2.6) | 0 | 0 | 0 | 1 (2.6) |
Loss 2 mechanical) | 8 (21.1) | 7 (18.4) | 4 (10.5) | 1 (2.6) | 20 (52.6) |
Loss 3 (both) | 5 (13.2) | 2 (5.3) | 0 | 0 | 7 (18.4) |
All | 20 (52.6) | 9 (23.7) | 5 (13.2) | 4 (10.5) | 38 (100) |
B Dorsal Foot | Gain 0(None) | Gain 1 (Thermal) | Gain 2 (Mechanical) | Gain 3(Both) | All |
Loss 0 (none) | 3 (7.9) | 0 | 6 (15.8) | 1 (2.6) | 10 (26.3) |
Loss 1 (thermal) | 2 (5.3) | 0 | 0 | 0 | 2 (5.3) |
Loss 2 mechanical) | 14 (36.8) | 1 (2.6) | 5 (13.2) | 0 | 20 (52.6) |
Loss 3 (both) | 5 (13.2) | 0 | 1 (2.6) | 0 | 6 (15.8) |
All | 24 (63.2) | 1 (2.6) | 12 (31.6) | 1 (2.6) | 38 (100) |
CDT = cold detection threshold; CPT = cold pain threshold; DMA = dynamic mechanical allodynia; Gain 0 = no gain of detection; Gain 1 = only thermal gain (HPT or CPT); Gain 2 = only mechanical gain (MPT, MPS, DMA, or PPT); Gain 3 = both thermal and mechanical gain; HPT = heat pain threshold; Loss 0 = no loss of detection; Loss 1 = only thermal loss (CDT or WDT); Loss 2 = only mechanical loss (MDT or VDT); Loss 3 = both thermal and mechanical loss; MDT = mechanical detection threshold; MPS = mechanical pain sensitivity; MPT = mechanical pain threshold; PPT = pain pressure threshold; WDT = warm detection threshold; VDT = vibration detection threshold.
A Dorsal Hand . | Gain 0(None)No. (%) . | Gain 1 (Thermal)No. (%) . | Gain 2 (Mechanical)No. (%) . | Gain 3(Both)No. (%) . | All No. (%) . |
---|---|---|---|---|---|
Loss 0 (none) | 6 (15.8) | 0 | 1 (2.6) | 3 (7.9) | 10 (26.3) |
Loss 1 (thermal) | 1 (2.6) | 0 | 0 | 0 | 1 (2.6) |
Loss 2 mechanical) | 8 (21.1) | 7 (18.4) | 4 (10.5) | 1 (2.6) | 20 (52.6) |
Loss 3 (both) | 5 (13.2) | 2 (5.3) | 0 | 0 | 7 (18.4) |
All | 20 (52.6) | 9 (23.7) | 5 (13.2) | 4 (10.5) | 38 (100) |
B Dorsal Foot | Gain 0(None) | Gain 1 (Thermal) | Gain 2 (Mechanical) | Gain 3(Both) | All |
Loss 0 (none) | 3 (7.9) | 0 | 6 (15.8) | 1 (2.6) | 10 (26.3) |
Loss 1 (thermal) | 2 (5.3) | 0 | 0 | 0 | 2 (5.3) |
Loss 2 mechanical) | 14 (36.8) | 1 (2.6) | 5 (13.2) | 0 | 20 (52.6) |
Loss 3 (both) | 5 (13.2) | 0 | 1 (2.6) | 0 | 6 (15.8) |
All | 24 (63.2) | 1 (2.6) | 12 (31.6) | 1 (2.6) | 38 (100) |
A Dorsal Hand . | Gain 0(None)No. (%) . | Gain 1 (Thermal)No. (%) . | Gain 2 (Mechanical)No. (%) . | Gain 3(Both)No. (%) . | All No. (%) . |
---|---|---|---|---|---|
Loss 0 (none) | 6 (15.8) | 0 | 1 (2.6) | 3 (7.9) | 10 (26.3) |
Loss 1 (thermal) | 1 (2.6) | 0 | 0 | 0 | 1 (2.6) |
Loss 2 mechanical) | 8 (21.1) | 7 (18.4) | 4 (10.5) | 1 (2.6) | 20 (52.6) |
Loss 3 (both) | 5 (13.2) | 2 (5.3) | 0 | 0 | 7 (18.4) |
All | 20 (52.6) | 9 (23.7) | 5 (13.2) | 4 (10.5) | 38 (100) |
B Dorsal Foot | Gain 0(None) | Gain 1 (Thermal) | Gain 2 (Mechanical) | Gain 3(Both) | All |
Loss 0 (none) | 3 (7.9) | 0 | 6 (15.8) | 1 (2.6) | 10 (26.3) |
Loss 1 (thermal) | 2 (5.3) | 0 | 0 | 0 | 2 (5.3) |
Loss 2 mechanical) | 14 (36.8) | 1 (2.6) | 5 (13.2) | 0 | 20 (52.6) |
Loss 3 (both) | 5 (13.2) | 0 | 1 (2.6) | 0 | 6 (15.8) |
All | 24 (63.2) | 1 (2.6) | 12 (31.6) | 1 (2.6) | 38 (100) |
CDT = cold detection threshold; CPT = cold pain threshold; DMA = dynamic mechanical allodynia; Gain 0 = no gain of detection; Gain 1 = only thermal gain (HPT or CPT); Gain 2 = only mechanical gain (MPT, MPS, DMA, or PPT); Gain 3 = both thermal and mechanical gain; HPT = heat pain threshold; Loss 0 = no loss of detection; Loss 1 = only thermal loss (CDT or WDT); Loss 2 = only mechanical loss (MDT or VDT); Loss 3 = both thermal and mechanical loss; MDT = mechanical detection threshold; MPS = mechanical pain sensitivity; MPT = mechanical pain threshold; PPT = pain pressure threshold; WDT = warm detection threshold; VDT = vibration detection threshold.
Paradoxical Heat Sensation
A total of 21 (55%) patients had PHS [28] in the lower extremity (13 in the oxaliplatin group and eight in the docetaxel group, P = 0.33). In the upper extremity, PHS was found in two patients in the oxaliplatin group and in one in the docetaxel group. When dividing the patients into two groups with and without PHS, patients with PHS had significantly lower WDT (more warm detection loss) than patients without abnormal PHS (P = 0.03, t test) (Figure 2C).
Intraepidermal Nerve Fiber Density
A total of 51 skin biopsies from the upper extremity (20 in the oxaliplatin group, 17 in the docetaxel group, and 14 in the control group) and 52 from the lower extremity (19 in the oxaliplatin group, 18 in the docetaxel group, and 15 in the control group) were available for IENFD count. Because five healthy controls (33.3%) had extremely low IENFD values (under 3 mm−1), we had a strong suspicion that at least a subset (and possibly all) of the IENFD values were unreliable. IENFD results from the skin biopsies are therefore omitted.
Nerve Conduction Studies
Supplementary Table 2 presents the results of the NCSs. The most common types of polyneuropathy were pure sensory neuropathy, which was found in 11 oxaliplatin- and four docetaxel-treated patients, and sensory-motor polyneuropathy, which was found in five patients in the oxaliplatin group and in one patient in the docetaxel group. The sensory polyneuropathy was primarily classified as axonal (Supplementary Table 2). Using our diagnostic criteria, 16 (80%) patients in the oxaliplatin group and five (28%) patients in the docetaxel group had a large fiber polyneuropathy defined by NCSs. In addition, three patients in each group had only one abnormal sensory nerve and therefore did not fulfill our diagnostic criteria for polyneuropathy. The patients in the oxaliplatin group had abnormal sensory nerves in both the upper and lower extremities, whereas the patients in the docetaxel group were mainly affected in the lower extremity.
Individual Results
The individual results of the clinical examinations together with patient-reported unpleasantness are presented in Supplementary Table 2. Estimated ordinal likelihood of distal symmetrical polyneuropathy was ++ ++ in 16 oxaliplatin- and five docetaxel-treated patients, +++ in one oxaliplatin-treated patient, ++ in three oxaliplatin- and six docetaxel-treated patients, and + in one oxaliplatin- and five docetaxel-treated patients [31]. The polyneuropathy was mainly a sensory axonal large fiber or mixed fiber polyneuropathy.
Discussion
In patients with chronic bilateral distal dysesthesia after treatment with adjuvant oxaliplatin following colorectal cancer or adjuvant docetaxel following breast cancer, the predominant sensory phenotype was loss of function affecting both upper and lower extremities, primarily on large fiber parameters, and in a minor proportion of patients also on small fiber parameters. Cold allodynia was the most common type of evoked pain, equally common following oxaliplatin and docetaxel treatment and most pronounced in the upper extremity. Figure 3 shows the frequency of abnormal QST values and can therefore easily be translated into clinical use. The most common symptoms in both lower and upper extremities were tingling (pins and needles), numbness, burning pain or discomfort with and without cold, and a greater than normal sense of touch, with no difference between the two groups. Symptoms were mainly described as unpleasant (dysesthesia), with 25% of patients in the oxaliplatin group and 56% in the docetaxel group describing their sensory symptoms as pain. Patients had mainly a sensory axonal large or mixed fiber polyneuropathy, which tended to be most severe in patients treated with oxaliplatin.
Sensory Phenotypes
Using QST to define patterns of sensory symptoms and questionnaires to define pain qualities is considered a promising method for subgrouping of patients to develop a mechanism-based treatment strategy [32,33]. We found that patients treated with oxaliplatin and docetaxel had very similar sensory phenotypes, comparable with the phenotypes seen in patients with HIV [18] and mixed polyneuropathy [19]. Despite the very different symptoms seen in the acute phase after oxaliplatin and docetaxel treatment [4,10], it was striking that the patients’ sensory profiles and clinical symptoms were very alike in the chronic phase (Figure 1). The most predominant sign was sensory loss to Aβ-mediated sensory modalities with decreased mechanical detection and vibration detection thresholds, and both groups had less thermal loss, as defined by cold and warm detection thresholds in the feet different than patients with HIV and mixed neuropathy [18,19]. The results indicated that the patients treated with oxaliplatin had slightly more sensory loss than those treated with docetaxel, although this was only significant for a few modalities.
Paradoxical Heat Sensation
Interestingly, more than 50% of patients had PHS in the lower extremity. Consistent with a previous study [34], we found that PHS was associated with higher warm detection thresholds. Another study found a correlation to higher cold detection thresholds [35], but no study has shown an association with pain thresholds, suggesting that PHS is related to thermal sensory loss. This may suggest that PHS is an indicator of small fiber loss rather than gain. This is supported by a study in healthy subjects, where PHS was seen after capsaicin application and was associated with higher WDTs and higher CDTs [36]. It was speculated that the occurrence of PHS was related to loss of tonic inhibition of type 2 C fiber pathways by decreased function of A delta cold fibers [36], but few studies have explored PHS and little is known about the underlying mechanisms. Abnormalities in thermal sensory limen were also slightly more common than abnormalities in cold and warm detection thresholds in our study. The results of thermal sensory limen and PHS are not included when using the coding system of gain and loss [19]. It should be further studied whether abnormalities in thermal sensory limen and the presence of PHS are sensitive markers of small fiber loss and may be early predictors of such.
IENFD
Unfortunately, the IENFD values in this study were found to be unreliable as a subset of healthy controls had unexplainable low values that were lower than in other studies from our laboratory. The reasons for this observation are not known but may be due to unidentified technical issues. Immunohistological stainings are difficult to standardize, which means that there are often variations both within and between laboratories. These differences can be caused by tissue preparation (e.g., the type of fixative or cryoprotectant used), temperature during cutting the biopsies, method of cutting (e.g., sliding microtome or cryostat), staining protocol (e.g., solutions used, incubation times, and concentration/type of antibodies), method of counting the nerve fibers, and a significant intraobserver difference in IENFD estimation. It is therefore recommended that each laboratory or study has its own control group and does not rely only on normal material from the literature, although the same staining protocol was used.
Dysesthesia and Pain and Association with Psychological Functioning
Dysesthesia is a common complaint in polyneuropathy [1]. In both groups, the intensity was on average to moderate in the feet and low to moderate in the hands with an impact on daily activities. Distal pain, which was most common in the feet, was reported by 25% of patients in the oxaliplatin group and 56% in the docetaxel group. Pricking, numbness, and burning were common descriptors in both groups. Numbness is a descriptor for sensory deafferentation and is often described in painful polyneuropathy [37].
Patients in both groups scored high on the EQ-5 D VAS compared with other chronic pain patients [38]. The results from the EQ-VAS as well as the HADS were, however, in line with those seen in other patients with peripheral neuropathy without pain [39]. Patients in both groups also scored lower on the PCS and the BPI than other patients with polyneuropathy [18]. One explanation could be that the patients in our study knew why they had developed neuropathy. We found no significant difference in patient-rated quality of life and pain interference between the two groups. Patients in the docetaxel group, however, scored significantly higher on depression and anxiety as well as on pain catastrophizing, including the subscales rumination and helplessness. Even when excluding men from the analysis to examine if gender was a confounder, we still found a significant difference in helplessness and anxiety. This result is supported by previous findings [4] and could be related to the age difference between the groups as it has been shown that younger age is related to an increased risk of depressive symptoms in breast cancer patients [40]. Others have shown that patients with breast cancer have higher HADS scores based on a higher fear of progression than patients with colon cancer [41].
Diagnosing Chemotherapy-Induced Neuropathy
Using our diagnostic criteria, 80% of the patients in the oxaliplatin group and 28% in the docetaxel group had polyneuropathy defined by NCSs, with the neuropathy being mainly an axonal sensory polyneuropathy consistent with other studies [5,22,42]. We used a conventional surface electrode technique including examination of distal nerves, but it is possible that using the near-nerve technique would have increased the number of patients with neurophysiologically defined polyneuropathy [43]. The lack of valid IENFD measures, and thus the lack of an independent measure of small fiber neuropathy, is a shortcoming of the study.
Adjuvant Oxaliplatin and Docetaxel
It is common to pool patients with different types of cancer, at different disease stages, and treated with different neurotoxic agents. We chose to study chronic chemotherapy-induced polyneuropathy following standard adjuvant chemotherapy in two groups of patients known to have different symptoms during treatment with chemotherapy. We chose to study patients in the adjuvant setting as this was a homogeneous group of patients. Patients treated with palliative chemotherapy often receive several types of chemotherapy, are treated for longer periods of time [44], and are willing to accept considerable side effects [45]. Moreover, palliative patients may have pain and discomfort for a number of reasons, for example, previous chemotherapy, metastases, other oncologic treatments, radiation therapy, and poor general health [46]. The patients in our two groups differed in age and gender, but the results from the NCSs and QST were compared with age- and gender-corrected normal material. Despite the effort to study a homogeneous group of patients with chemotherapy-induced pain and dysesthesia, it is an important limitation to our study that the two groups of patients had different adjuvant oncologic treatments. Musculoskeletal pain is common in cancer patients treated with chemotherapy [47]; however, patients often receive other treatments that may cause pain. In particular, breast cancer patients treated with docetaxel often have other types of pain related to adjuvant endocrine therapy, which may be difficult to separate from pain related to chemotherapy-induced neuropathy [4].
Both oxaliplatin-induced and docetaxel-induced polyneuropathies represent a significant problem that affects the daily life of patients. Pain was reported less often than dysesthesia, and it is therefore important to include questions about dysesthesia in the follow-up of these patients. Patients in both groups mainly had a sensory, axonal large, or mixed fiber polyneuropathy, which tended to be most severe in the oxaliplatin group. The sensory symptoms and somatosensory profiles were very similar, with loss of large fiber function and cold allodynia in the hands being the most common type of evoked pain, present in about one-third of patients. This result supports the suggestion of both chemotherapies’ affection DRG cells in chronic CIPN. This result shows that despite the very different development of neuropathic symptoms during chemotherapy, it seems reasonable to pool these two groups of patients in the case of definite chemotherapy-induced peripheral neuropathy as established by clinical examination. The differences in psychological functioning are probably not related to the patients’ polyneuropathy and need further investigation.
Funding source: This study is part of the Europain Collaboration, which has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115007, resources of which are composed of a financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. The study has also received funding from Radiumstationens Forskningsfond, Region Midtjyllands Sundhedsvidenskabelige Forskningsfond, and Frits, Georg og Marie Cecilie Gluds Legat. Pall Karlsson is funded by the Danish Diabetes Academy, supported by the Novo Nordisk Foundation and an unrestricted grant from Astellas.
Conflicts of interest: The authors disclose no potential conflicts of interest.