Background Oxaliplatin is a platinum compound that is widely used in the treatment of some solid tumours. Oxaliplatin-induced peripheral neuropathy (OIPN) in the upper and lower extremities is the major adverse side effect and represents the main dose-limiting factor of this drug. The aim of this single-arm study was to evaluate the feasibility and effects of laser acupuncture (LA) in the treatment of OIPN in patients with advanced gastrointestinal cancers.
Methods 17 gastrointestinal cancer survivors (14 colorectal and 3 gastric cancers), who had been treated with oxaliplatin-based chemotherapies, were recruited. Low-level laser stimulation (50 mW) bilaterally at PC6, PC7, PC8, P9, LU11, SP6, KI3, BL60, KI1, and KI2 was administered for 20 min/point for 12 sessions over 4 weeks. The pain quality assessment scale (PQAS), chemotherapy-induced neurotoxicity questionnaire (CINQ), oxaliplatin-specific neurotoxicity scale (OSNS), quantitative touch-detection threshold (using von Frey filaments), and cold-triggered pain withdrawal latency (using the cold-water immersion test) were measured before and after completion of the 12 treatment sessions.
Results PQAS, CINQ, and OSNS scores, as well as touch-detection threshold and cold-trigger pain withdrawal latency all improved significantly after LA in the cancer patients with OIPN (p<0.05). LA significantly relieved both oxaliplatin-induced cold and mechanical allodynia and also decreased the incidence and severity of neurotoxicity symptoms in the patients' upper and lower extremities and impact on their daily activities (all p<0.05).
Conclusions Following treatment with LA, neurotoxicity symptoms were significantly improved in cancer patients with OIPN. Further randomised controlled trials are needed to evaluate the role of LA as a therapeutic option in the management of OIPN.
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Oxaliplatin is a platinum-based cytotoxic agent that is used as a first line therapy in the treatment of various metastatic gastrointestinal cancers, including gastric cancer (GC) and colorectal cancer (CRC).1 However, oxaliplatin has a unique neurotoxic pattern of side effects unrelated to that observed with other therapeutic platinum derivatives. Oxaliplatin-induced peripheral neuropathy (OIPN) consists of a rapid-onset acute sensory neuropathy and late-onset cumulative sensory neuropathy that occurs after several cycles of therapy.2 ,3 Neuropathic pain, with symptoms of paraesthesia or dysaesthesia that are triggered by cold (acute neuropathy) or present as a loss of sensation, dysaesthesia, and even functional impairment (chronic neuropathy), is commonly experienced by patients treated with oxaliplatin.4 Typically, a multidisciplinary pharmacological approach is employed to manage OIPN-induced pain, including allodynia and hyperalgesia, but effective pharmacological therapies are still lacking and few can be recommended for adoption into clinical practice.5 At the same time, exploration of non-pharmacological treatments, which may provide new opportunities for treating neuropathic symptoms, are needed.
Acupuncture has a wide range of potential uses in oncology6–9 and is also effective in treating various types of peripheral neuropathy,10–13 including chemotherapy-induced peripheral neuropathy (CIPN). The results of multiple trials suggest that manual acupuncture (MA), electroacupuncture (EA), and pharmacopuncture may alleviate neuropathic symptoms induced by chemotherapy.10 ,14–16 Most studies, however, involve invasive procedures requiring the insertion of thin needles that are subsequently manipulated manually or electrically. Laser acupuncture (LA) is a related technique that offers non-invasive somatosensory stimulation with the advantage that the skin does not need to be punctured; it is currently being used and/or evaluated for a wide range of different conditions (outside of oncology).17–20 Several studies have demonstrated that LA significantly reduces neuropathic pain in patients with carpal tunnel syndrome,21 ,22 but, to our knowledge, no studies to date have focused on cancer patients with OIPN.
The purpose of this study was to evaluate the effects of LA on neurotoxicity symptoms, including neuropathic pain and paraesthesia, induced by oxaliplatin-based chemotherapies in patients with gastrointestinal cancer.
The study was conducted at China Medical University, in Taiwan, in accordance with the Declaration of Helsinki and Guidelines for Good Clinical Practice. The research protocol was reviewed and approved by the Institutional Review Board of China Medical University (reference no. DMR100-IRB-288). Written informed consent was obtained from all study participants before enrolment.
This was a pilot prospective cohort study with pre- and post-intervention design. Patients with a diagnosis of GC or CRC were routinely referred from the Department of Medical Oncology at Cheng Ching General Hospital and Chung Shan University Hospital. The patients were then referred to one of three research therapists at China Medical University for assessment of eligibility and intervention. LA was administered three times per week for 4 weeks. Outcome measures, including oxaliplatin-induced neurotoxicity, pain quality, mechanical touch-detection threshold, and cold-triggered pain withdrawal latency before (pre-treatment) and after (post-treatment) the 12 sessions of LA were assessed by two randomly assigned members of our research team. Data were analysed by a researcher and physician (Y-LH and C-CY) who were blinded to the participants' treatment status. A schematic diagram of the experimental design is presented in online supplementary figure S1.
Flow chart of study participants with oxaliplatin-induced peripheral neuropathy (OIPN).
To meet the eligibility criteria, participants needed to: (1) be at least 18 years of age; (2) have been treated with oxaliplatin-based regimens for stages II–IV GC or CRC, including one of the following treatment regimens: standard infusion of fluorouracil, leucovorin and oxaliplatin (FOLFOX 4; oxaliplatin dose of 85 mg/m2); infusion of fluorouracil, leucovorin and oxaliplatin (FOLFOX 6; oxaliplatin dose of 100 mg/m2) or capecitabine plus oxaliplatin (XELOX; oxaliplatin dose of 130 mg/m2); (3) have no history of neuropathy before oxaliplatin treatment; (4) have no documented or observable psychiatric or neurological disorders that might interfere with study participation (eg, dementia or psychosis); and (5) have grade 2 or higher neuropathy (dysaesthesia), according to the ‘Nervous System Disorders’ category of the Common Terminology Criteria for Adverse Events, v4.0. Exclusion criteria were: another malignancy; life expectancy <3 months; and severe or unstable cardiorespiratory or musculoskeletal disease. Participants had to remain on the same medications throughout the study period, but minor adjustments in dosage were allowed.
The treatment methods (ie, point selection, type of stimulation, and treatment schedule) were chosen by a panel of expert faculty from the School/College of Chinese Medicine, China Medical University. Patients received LA three times per week for four consecutive weeks (total of 12 sessions over 4 weeks). Two licensed physical therapists (S-FH and YCC) with over 10 years' combined experience provided all treatments.
Acupuncture points were located using an acupuncture point detection unit (No. 2779, DJO Chattanooga Group, USA). Patients were treated in a comfortable supine position. Treatment was administered by 10-channel Ga-Al-As diode laser (Class IIIb by the old system classification of ANSI Z136.1, Konftec Corporation, Taipei, Taiwan) with a wavelength of 780 nm at 100 Hz (pulsed mode, 10% of output duration). Spot size was approximately 0.2 cm2, and output power of the laser irradiation was 80 mW per session. Bilateral upper and lower extremities were treated. The acupuncture points selected specifically for this study were PC6 (Neiguan), PC7 (Daling), PC8 (Laogong), PC9 (Zhongchong), and LU11 (Shaoshang) in the upper extremities, and SP6 (Sanyinjiao), KI3 (Taixi), BL60 (Kunlun), KI1 (Yongquan), and KI2 (Rangu) in the lower extremities. After the patient experienced de qi (a sensation of soreness, numbness, tingling, or warmth at the sites of laser irradiation),23 the treatment was continued for 20 min. The energy density was 48 J/cm2 per session. The output of the equipment was routinely checked before each treatment session using a laser check power meter (Coherent Inc, Santa Clara, California, USA). The patients were treated three times per week for a total of 12 sessions, which represented a cumulative laser energy of 115.2 J per patient.
The oxaliplatin-specific neurotoxicity scale (OSNS) was used as a specific measure of oxaliplatin-induced neurotoxicity, with the following grades: neuropathic symptoms of dysaesthesia or paraesthesia resolving completely within 7 days (grade 1); symptoms persisting for longer than 7 days (grade 2); symptoms leading to functional impairment (grade 3).24 ,25 In addition, a chemotherapy-induced neurotoxicity questionnaire (CINQ) characterising the incidence and severity of neurotoxicity symptoms in the participant's upper and lower extremities and the impact on their daily activities was recorded.26 In the questionnaire, each symptom question was followed by a question about the degree of difficulty experienced and the influence on daily activities measured using a 1 to 5 numeric rating score (NRS); a higher score indicated more severe neurotoxicity symptoms.
All study participants responded to the descriptor items for assessment of pain quality in the 20-item pain quality assessment scale (PQAS) with the 0 to 10 NRS scale, in which 0=‘no pain’ or ‘not (sensation/item)’ and 10=‘the most (descriptor) pain sensation imaginable.’
Quantitative touch-detection threshold
Quantitative sensation of touch detection was used to test sensory levels and obtain objective data on the status of diminishing or returning sensibility. Touch detection was measured using von Frey monofilaments (NC-12775-99, Touch-Test Sensory Evaluators, North Coast Medical, Inc, USA), with weights from 0.008 g to 300 g at the bases of the plantar and palmar sides of each toe and both sides of the fingertips. The well-known up-down method27 ,28 was applied to measure touch-detection thresholds.
Quantitative cold-triggered pain withdrawal latency
For patients who described cold allodynia in the PQAS assessment, this was further assessed using the hand immersion test in a water bath maintained at 10°C, followed by a touch-detection test. The patient was allowed to acclimate for 15 min in a room with a temperature of 25–26°C and then instructed to immerse both hands in cold water. The hand-withdrawal latency was recorded when the patient felt cold pain and again when he/she could no longer tolerate the pain. After the cold-water immersion test, each patient's hand was immersed in warm water at 37°C for 10 min of re-warming. A cold-triggered pain withdrawal latency of more than 10 s was considered normal.
Data relating to patients' clinical characteristics are expressed as mean±SD; data from rating scales are expressed as mean±SEM or as frequencies and percentages for categorical variables. Individual CINQ and PQAS questionnaire items scored positively by ≥47.1% of patients (8/17) at baseline were selected as the main outcome measures, as described by Wang et al.29 Continuous variables were analysed using the paired t-test, and data with an ordinal scale were analysed using the Wilcoxon signed-rank test, depending on whether or not the data were normally distributed. A value of p<0.05 was considered statistically significant. All data were analysed using the Statistical Package for the Social Sciences (SPSS) V.20.0 for Windows (SPSS Inc, Chicago, Illinois, USA).
Seventeen patients (nine male and eight female) who met the eligibility criteria with the presence of OIPN symptoms, including pain, numbness, and tingling in the hands and feet, agreed to participate. All patients completed 12 sessions of LA treatment and were included in the analysis. No patients reported any serious adverse event related to LA. Demographic data and clinical characteristics of the eligible participants are shown in table 1. The participants were 66.5±8.4 (range 40–81.8) years of age. Patients' oxaliplatin-based chemotherapy had been completed 2.32±1.05 years before their participation in the study. None of the demographic variables was significantly associated with symptoms of neuropathy.
Effects of LA on oxaliplatin-induced neurotoxicity
The percentage frequency and intensity of impairments in selected OSNS and CINQ items at the pre- and post-treatment time points, and the frequency of patients whose symptoms improved or were unchanged after LA, are shown in tables 2 and 3. After the LA intervention, 58.8% of participants had an improvement of at least one grade, and 42.2% experienced no change. LA significantly improved OSNS grading compared with pre-treatment values (p<0.05).
Before the LA intervention, 12 of 19 components (63.2%) of the CINQ questionnaire items were present in ≥47.1% of patients in the study population (our preset threshold) and are detailed in table 3. The frequency and intensity of these selected CINQ component scores in the upper and lower extremity categories were significantly decreased after LA, including senses of tingling, numbness, being able to distinguish between rough and smooth surfaces, and hot versus cold, when compared with values before treatment (all p<0.05). Impairments affecting daily activities were also significantly decreased after treatment (all p<0.05).
Effects of LA on pain quality
The frequency of impairments and mean rating scales for the PQAS at pre- and post-treatment time points are presented in table 4. Before the LA intervention, nine of 20 components (45.0%) of the PQAS questionnaire (including sharp, dull, cold, numb, electrical, tingling, cramping, heavy and unpleasant pain sensations) were reported by ≥47.1% of patients in the study population. The rating scales of all nine PQAS components were significantly decreased after treatment compared with the rating scales before treatment (all p<0.05).
Effects of LA on quantitative touch-detection threshold and cold-triggered pain withdrawal latency
As shown in figure 1A, there were elevated touch-detection thresholds (>0.07 g above normal hand and dorsal foot thresholds) when assessed using von Frey filaments at five fingertips and toes. After treatment, touch-detection thresholds in bilateral fingertips and toes were significantly decreased when compared with those before treatment (all p<0.05). Among eight patients who described cold allodynia in the PQAS assessment and therefore underwent the 10°C cold-water immersion test, cold-triggered pain withdrawal latency was significantly increased compared with that before treatment (p<0.05; figure 1B).
In the present study, repeated application of LA was associated with a reduction in oxaliplatin-induced neuropathic pain, cold-triggered pain, and mechanical allodynic responses in the qualifiers of PQAS scores, the cold-water (<10°C) limb-immersion test, and the von Frey test. In addition, the severity of OIPN, measured using OSNS and CINQ scores, was reduced after LA, and the treatment also attenuated the impact of neurotoxicity on the patients' daily activities. Thus, LA might improve neuropathic pain and paraesthesia induced by oxaliplatin-based chemotherapy in patients with cancer.
Multiple observational and interventional studies support the potential efficacy or effectiveness of acupuncture in the treatment of CIPN and OIPN; however, many studies to date have been small and not sham-controlled.14 ,16 ,30 ,31 In one prospective case series, five patients with CIPN induced by carboplatin and paclitaxel were treated with MA at CV6 (Qihai), ST36 (Zusanli), LI11 (Quchi), Bafeng, and Baxie for two 6-week cycles, separated by 4 weeks; all patients reported an improvement in sensation, gait, and balance and were able to decrease their doses of pain medications.14 A retrospective case series examined 18 patients with CIPN caused by a variety of chemotherapy agents; patients were treated with six weekly acupuncture sessions at SP6, ST36, and LR3 (Taichong); 14 (82%) patients reported an improvement in their symptoms with acupuncture.30 A small pilot trial reported on six patients receiving 10 weeks of MA, compared with five control patients who received standard care; five of the patients treated with MA at ST34 (Liangqiu), Qiduan, and Neihuaijian over 10 weekly sessions reported general improvement in symptoms as compared with two patients in the control group.31 In a randomised controlled trial of 64 patients with CIPN induced by paclitaxel or oxaliplatin, patients were randomised to treatment with MA at LI4 (Hegu), LR3, ST36, CV6, and LI11 or treatment with cobamamide; 20 (66.7%) patients in the acupuncture group significantly improved, a response that was superior to that of 12 (40.0%) patients in the control group treated with medication.32 A single arm non-randomised pilot trial examined 19 patients with CIPN induced by thalidomide/bortezomib treated by 20 treatment sessions of EA at LI4, SI3 (Houxi), Baxie, LR3, SP6, GB42 (Diwuhui), ST36, Bafeng, GV20 (Baihui), CV4 (Guanyuan), and CV6 over 9 weeks; the scores of patient-reported outcomes and pain severity were improved significantly after EA.33 In our study, GC and CRC patients with OIPN treated with LA demonstrated a significant improvement in neuropathic pain and paraesthesia in the extremities, especially tingling, numbness, cold-triggered pain, cold allodynia, touch detection, and feeling of heaviness in the legs.
Animal studies have demonstrated that EA significantly inhibits paclitaxel- and oxaliplatin-induced allodynia and hyperalgesia through spinal opioid receptors.34 ,35 Analgesia can also be induced by low-level laser through modulation of peripheral opioid receptors.36 In our previous study in rats,28 low-level laser therapy, targeted at the skin surfaces directly above sites where peripheral nerves are distributed, relieved both cold and mechanical allodynia induced by oxaliplatin. This effect was achieved by modulation of protein levels of nerve growth factor and transient receptor potential M8 in dorsal root ganglion neurons, as well as substance P in the spinal dorsal horn. Based on these animal studies, it seems possible that the action of LA on OIPN symptoms of hyperalgesia, cold allodynia, and pain are mediated by enhancement of spinal/central opioid systems and modification of substance P, nerve growth system, and transient receptor potential M8.
As our study was only designed to be an initial exploration of the effects of LA on the management of OIPN, it has many limitations that must be acknowledged. The major limitations were the very small sample size and uncontrolled design. The safety and effectiveness of LA needs further investigation in a large randomised controlled trial. With respect to measurement tools, we recommend that future prospective studies should consider incorporating the European Organization for the Research and Treatment of Cancer QLQ-C30 (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaires to evaluate the impact of LA and related interventions on the subjective health and well-being (health-related quality of life) of patients treated with oxaliplatin-based chemotherapy, and to determine the efficacy of LA for treatment of this problem.
In conclusion, the findings of this preliminary study suggest that LA alleviates OIPN-induced neuropathic pain and paraesthesia in patients with gastrointestinal cancer and may be an effective non-invasive strategy for this serious adverse effect. This strategy deserves further study via rigorously controlled, larger-scale, long-term trials.
Contributors All authors contributed to the study's conception/design, data collection, data analysis and interpretation, were involved in drafting and revising the manuscript, approved the final version of the manuscript for publication, and accept responsibility for the accuracy and integrity of all aspects of the research. Y-LH, C-CY and W-FC are the grant holders.
Funding The study was funded by grants from the Ministry of Science and Technology [NSC101-2314-B-039-003-MY2] and Cheng Ching General Hospital [CH10500197] in Taiwan.
Competing interests None declared.
Patient consent Obtained.
Ethics approval The protocol for this study was approved by the ethical review committee of China Medical University, Taichung, Taiwan (reference no. DMR100-IRB-288).
Provenance and peer review Not commissioned; externally peer reviewed.
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