Neuropathic Pain Features in Patients with Bone Metastases

doi:10.1016/j.clon.2015.10.007

Clinical Oncology

Volume 28, Issue 3, March 2016, Pages 204-208

https://doi.org/10.1016/j.clon.2015.10.007 Get rights and content

Highlights

•
A cohort survey to estimate the prevalence of neuropathic pain was conducted.
•
Patients were prospectively assessed by the validated screening questionnaire.
•
A considerable proportion of patients were proven to have neuropathic pain.

Abstract

Aims

The results of previous randomised controlled trials suggest that radiation oncologists should consider the presence of neuropathic pain when they prescribe dose fractionations for painful bone metastases. Although validated screening tools for neuropathic pain features are currently available, the prevalence of such features among patients with painful bone metastases is still poorly understood. The purpose of this study was to estimate the prevalence of neuropathic pain features among patients who received palliative radiotherapy for painful bone metastases.

Materials and methods

We conducted a cohort survey of consecutive patients who received palliative radiotherapy for painful bone metastases at St Luke's International Hospital between 2013 and 2014. Patients were prospectively assessed before radiotherapy using the validated screening questionnaire to identify neuropathic pain components in Japanese patients. Pain with neuropathic features was prospectively defined using the total score of the seven-item questionnaire and a cut-off score ≥9. The pain response was assessed 2 months after the start of radiotherapy according to the criteria defined by the International Bone Metastases Consensus Working Party.

Results

Eighty-seven patients were assessed. Twenty-four per cent of patients (95% confidence interval: 16–35%) were diagnosed as having pain with neuropathic features. On multivariate analysis, no significant correlations were seen between neuropathic pain features and patient characteristics. Sixty-four patients (74%) were assessable 2 months after the start of radiotherapy. Overall response rates were 59% (95% confidence interval: 33–82%) in patients with neuropathic features and 55% (95% confidence interval: 40–70%) in those without such features.

Conclusions

A considerable proportion of the patients were proven to have bone pain with neuropathic features. Further investigations are warranted to validate symptom assessment tools in cooperation with pain distribution and image findings, and to clarify if the presence of neuropathic pain affects the response to palliative radiotherapy.

Introduction

Radiotherapy provides successful palliation of painful bone metastases, with 50–80% overall response rates [1]. Numerous prospective randomised controlled trials have shown the equivalence of multifraction and single-fraction radiotherapy for the palliation of painful bone metastases [2], [3], [4], [5], [6], [7], [8]. Owing to patient convenience, available resource advantage and cost-effectiveness, clinical practice guidelines have recommended that single-fraction radiotherapy should be standard care [9], [10], [11].

Neuropathic pain due to bone metastases has been the subject of one randomised trial comparing an 8 Gy single-fraction arm with a multifraction arm (20 Gy in five fractions) [12]. The intention-to-treat overall response rates for all 272 patients were 53% for the 8 Gy single-fraction arm and 61% for the multifraction arm (P = 0.18), whereas response rates for the 245 patients treated according to protocol were 53% for the 8 Gy single-fraction arm and 64% for the multifraction arm (P = 0.092). Although the response rates were not significantly different between the two arms, the lower limit of the 90% confidence interval for the difference in response rates (−18 to +2%) was below the pre-defined lower level of −15%. Furthermore, the trial may have been underpowered to detect a true effect for dose escalation due to an erroneously small sample size. The authors concluded that the 8 Gy single fraction was neither as effective as, nor less effective than, 20 Gy in five fractions, and that it may be reasonable in general to recommend a multifraction regimen for patients with bone metastases causing neuropathic pain.

According to these findings, radiation oncologists should consider the presence of neuropathic pain when they prescribe dose fractionations for painful bone metastases.

Recently, neuropathic pain was strictly defined [13], [14], [15], and validated screening and measurement tools are now available [16], [17], [18]. However, the presence of neuropathic pain features among patients with painful bone metastases is still poorly understood.

The primary objective of this study was to estimate the prevalence of neuropathic pain features among patients who received palliative radiotherapy for painful bone metastases. We also assessed patient characteristics and the pain response to radiotherapy associated with neuropathic features.

Section snippets

Materials and Methods

Results

All eligible patients completed the screening questionnaire. Eighty-seven patients were assessed. Patient characteristics are shown in Table 2. Pain medication use in evaluated patients is detailed in Table 3. Twenty-four per cent of patients (95% confidence interval: 16–35%) were diagnosed as having pain with neuropathic features. On multivariate analysis, higher NRS pain scores before radiotherapy (P = 0.08) and no use of bone-modifying agents (P = 0.054) were marginally correlated with

Discussion

In our study, about one-quarter of patients who received palliative radiotherapy for painful bone metastases showed neuropathic pain features. This was similar to the previous report by Kerba et al. [22], in which 17% (95% confidence interval: 10–24%) of patients had neuropathic pain features evaluated by S-LANSS.

As described in the Introduction, the investigators of the Trans-Tasman Radiation Oncology Group (TROG) 96.05 trial concluded that it may be reasonable in general to recommend a

Acknowledgements

This study was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan (24591860), and by Health Science Research Grants from the Ministry of Health and Welfare. In addition, this study was supported in part by the National Cancer Center Research and Development Fund (25-A-10).

References (23)

E. Chow et al.
Update on the systematic review of palliative radiotherapy trials for bone metastases
Clin Oncol (R Coll Radiol)
(2012)
E. Steenland et al.
The effect of a single fraction compared to multiple fractions on painful bone metastases: a global analysis of the Dutch Bone Metastasis Study
Radiother Oncol
(1999)
S. Kaasa et al.
Prospective randomised multicenter trial on single fraction radiotherapy (8 Gy x 1) versus multiple fractions (3 Gy x 10) in the treatment of painful bone metastases
Radiother Oncol
(2006)
P. Price et al.
Prospective randomised trial of single and multifraction radiotherapy schedules in the treatment of painful bony metastases
Radiother Oncol
(1986)
O.S. Nielsen et al.
Randomized trial of single dose versus fractionated palliative radiotherapy of bone metastases
Radiother Oncol
(1998)
S. Lutz et al.
Palliative radiotherapy for bone metastases: an ASTRO evidence-based guideline
Int J Radiat Oncol Biol Phys
(2011)
D.E. Roos et al.
Randomized trial of 8 Gy in 1 versus 20 Gy in 5 fractions of radiotherapy for neuropathic pain due to bone metastases (Trans-Tasman Radiation Oncology Group, TROG 96.05)
Radiother Oncol
(2005)
R. Baron et al.
Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment
Lancet Neurol
(2010)
M.I. Bennett et al.
The S-LANSS score for identifying pain of predominantly neuropathic origin: validation for use in clinical and postal research
J Pain
(2005)
D. Bouhassira et al.
Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4)
Pain
(2005)

E. Chow et al.

International consensus on palliative radiotherapy endpoints for future clinical trials in bone metastases

Radiother Oncol

(2002)

Cited by (11)

Pain Response Rates After Conventional Radiation Therapy for Bone Metastases Assessed Using International Consensus Pain Response Endpoints: A Systematic Review and Meta-Analysis of Initial Radiation Therapy and Reirradiation
2023, International Journal of Radiation Oncology Biology Physics
Previous meta-analysis of conventional radiation therapy for painful bone metastases showed overall response (OR) rates of 72% to 75% (evaluable patients), 61% to 62% (intent-to-treat patients) for initial radiation therapy, and 68% for reirradiation (evaluable patients). However, the definition of pain response differed among the studies included. Hence, we conducted a systematic review and meta-analysis to determine the pain response rates assessed by the International Consensus Pain Response Endpoints (ICPRE) for both initial radiation therapy and reirradiation. The PubMed and Scopus databases were searched for articles published between 2002 and 2021. The inclusion criteria were (1) prospective studies or studies based on prospectively collected data and (2) studies in which pain response was assessed using ICPRE. Our primary outcomes of interest were the OR rates (sum of the complete and partial response rates) for both initial radiation therapy and reirradiation. Of the 6470 articles identified in our database search, 32 and 3 met the inclusion criteria for the analysis of initial radiation therapy and reirradiation, respectively. The OR rates of initial radiation therapy in evaluable patients (n = 4775) and intent-to-treat patients (n = 6775) were 60.4% (95% confidence interval [CI], 55.2-65.4) and 45.4% (95% CI, 38.7-52.4), respectively. The OR rates of reirradiation in evaluable patients (n = 733) and intent-to-treat patients (n = 1085) were 70.8% (95% CI, 15.7-96.9) and 62.2% (95% CI, 5.3-98.0), respectively. Subgroup analyses of initial radiation therapy including the comparison of randomized and nonrandomized studies showed no significant differences in any comparison, indicating similar response rates across different study designs. For initial radiation therapy, we determined the ICPRE-assessed response rates, which were lower than previously reported. The OR and complete response rates should be benchmarks for future randomized and nonrandomized studies. For reirradiation, the wide CIs demonstrate that the response rates based on ICPRE require further investigation.
Clinical Predictors for Analgesic Response to Radiotherapy in Patients with Painful Bone Metastases
2021, Journal of Pain and Symptom Management
Citation Excerpt :
The use of corticosteroids was a negative predictor for RT response. In a systematic review, Gardner et al. identified eight studies evaluating clinical predictors for RT response.4,5,7,9-11,33-35 Only two studies, both secondary analyses, included several potential predictors in a multivariate analysis.4,5
Radiotherapy (RT) reduces pain in about 60% of patients with painful bone metastases, leaving many patients without clinical benefit. This study assesses predictors for RT effectiveness in patients with painful bone metastases.
We included adult patients receiving RT for painful bone metastases in a multicenter, multinational longitudinal observational study. Pain response within 8 weeks was defined as ≥2-point decrease on a 0−10 pain score scale, without increase in analgesics; or a decrease in analgesics of ≥25% without increase in pain score. Potential predictors were related to patient demographics, RT administration, pain characteristics, tumor characteristics, depression and inflammation (C-reactive protein [CRP]). Multivariate logistic regression analysis with multiple imputation of missing data were applied to identify predictors of RT response.
Of 513 eligible patients, 460 patients (90 %) were included in the regression model. 224 patients (44%, 95% confidence interval (CI) 39%−48%) responded to RT. Better Karnofsky performance status (Odds ratio (OR) 1.39, CI 1.15−1.68), breast cancer (OR 2.54, CI 1.12−5.73), prostate cancer (OR 2.83, CI 1.27−6.33) and soft tissue expansion (OR 2.00, CI 1.23−3.25) predicted RT response. Corticosteroids were a negative predictor (OR 0.57, CI 0.37−0.88). Single and multiple fraction RT had similar response. The discriminative ability of the model was moderate; C-statistic 0.69.
This study supports previous findings that better performance status and type of cancer diagnosis predicts analgesic RT response, and new data showing that soft tissue expansion predicts RT response and that corticosteroids is a negative predictor for RT response in patients with painful bone metastases.
Pain Response Rates After Conventional Radiation Therapy for Bone Metastases in Prospective Nonrandomized Studies: A Systematic Review
2019, Practical Radiation Oncology
This study aimed to determine the pain response rates after conventional radiation therapy (RT) for painful bone metastases in prospective nonrandomized studies, which better reflect daily practice than randomized controlled trials.
A literature search was conducted in PubMed and Scopus for articles published between 2002 and 2018. We only included articles in which pain response after RT was assessed using the International Consensus Endpoint initially published in 2002, or the updated version from 2012. In addition, to be included in this review, the study design was required to be prospective or based on prospectively collected data. Our primary outcomes of interest were the overall and complete response rates after conventional RT for bone metastases.
Of the 2863 articles identified in our database search, 12 met the inclusion criteria. Six studies excluded patients with features of complicated bone metastases. Only 2 papers reported exclusion criteria regarding analgesic use. Radiation schedules that were frequently used were 1 × 8 Gy, 5 × 4 Gy, and 10 × 3 Gy. The overall response rate in evaluable patients was 55%, and 754 of the 1379 evaluable patients experienced a complete or partial response. The complete response rate was 15% (196 of 1348 evaluable patients). In the intent-to-treat patient group, the overall response rate was 29% (754 of 2559 enrolled patients), and the complete response rate 8% (196 of 2528 enrolled patients).
We determined the pain response rates after conventional RT for painful bone metastases in prospective nonrandomized studies. The present review may provide benchmarks for future nonrandomized studies that investigate palliative RT for bone metastases.
A systematic review examining clinical markers and biomarkers of analgesic response to radiotherapy for cancer-induced bone pain
2019, Critical Reviews in Oncology/Hematology
Citation Excerpt :
In 2016 Nakamura et al. published a prospective study comparing pain response after XRT in patients with neuropathic pain features compared to patients without these features. ( Nakamura et al., 2016) Eighty-seven patients were included, and the patients were assessed before XRT (baseline) and at two months post-XRT (follow-up). Neuropathic pain was assessed using a screening questionnaire validated to identify neuropathic pain components in Japanese patients.
Cancer frequently spreads to bone, causing cancer-induced bone pain (CIBP) which affects quality of life. The best treatment is radiotherapy (XRT), but response is variable. The aim of this systematic review was to identify factors that predict analgesic response.
Using PRISMA guidelines, Medline (1946–2018), Embase Classic + Embase (1947–2018) and Cochrane (setup-2018) databases were searched. Eligible studies examined adult patients receiving external beam XRT for CIBP with clinical marker and/or biomarkers evaluated.
Twenty-one studies (n = 4490) were included: Urinary markers in three studies (n = 357), genomic biomarkers in one study (n = 107), imaging techniques in five studies (n = 231) and demographics and disease parameters in eight studies (n = 4572). Quantitative sensory testing (n = 23) and physical activity and/or gait (n = 42) have been examined in one study each, while two studies have evaluated grade of spinal instability (n = 276).
No predictors of analgesic response from XRT in CIBP were identified but several show promise.
A neuropathic pain component as a predictor of improvement in pain interference after radiotherapy for painful tumors: A secondary analysis of a prospective observational study
2018, Clinical and Translational Radiation Oncology
We previously demonstrated that patients with a tumor-related neuropathic pain component were more likely to experience a pain response after radiotherapy (RT) than those without. It is unknown whether the presence of a neuropathic component also favorably influences pain interference. In a secondary analysis of our previous prospective observational study, we investigated if the presence of a neuropathic component of the index pain caused by the irradiated tumors predicts greater reduction in pain interference.
For patients scheduled for RT for painful tumors, Brief Pain Inventory data were collected at initiation of RT and 1, 2, and 3 months thereafter. Multivariable linear regression analyses were performed to investigate the effects of the presence of a neuropathic component on the changes in pain interference scores (i.e., follow-up minus baseline). We used 10 covariates as potential confounders.
Of the 302 analyzable patients, 93 (31%) were diagnosed as having a neuropathic component of the index pain. Multivariable linear regression analyses revealed that all the point estimates of regression coefficients at 1-, 2-, and 3-month follow-up were negative values; some were statistically significant. At 2-month follow-up, patients with a neuropathic component experienced greater reductions in their pain interference scores for walking ability (p = 0.048), normal work (p = 0.021), sleep (p = 0.001), and enjoyment of life (p = 0.010) than those without it.
The presence of a neuropathic pain component predicted a greater reduction in pain interference after RT. Patients with neuropathic tumor-related pain should be offered the option of receiving palliative RT.
Predictors of Pain Palliation After Radiation Therapy for Painful Tumors: A Prospective Observational Study
2018, International Journal of Radiation Oncology Biology Physics
Citation Excerpt :
A study of 87 patients who received palliative RT for painful bone metastases showed that the overall response rates were 59% in patients with neuropathic features and 55% in those without such features (20). Patients were assessed using a validated screening questionnaire to identify neuropathic pain components (20). A study of 37 patients with malignant pleural mesothelioma showed that the presence of neuropathic pain (clinically or by Leeds Assessment of Neuropathic Symptoms and Signs) did not predict the response to RT (21).
Although radiation therapy (RT) is an important part of treatment for cancer pain, prediction of the patient's pain response remains difficult. We evaluated the characteristics of patients, their tumors, and their pain to identify the predictors of pain palliation after RT for painful tumors.
Our 3-center prospective observational study included patients scheduled for palliative or curative RT for painful tumors. Brief Pain Inventory data were collected at the start of RT and 1, 2, and 3 months thereafter. The pain response was assessed using the International Consensus Endpoint. The Mann-Whitney U-test was used to compare responders and nonresponders based on changes in the BPI scores. Predictors of the pain response were evaluated using the Fine-Gray model, in which death without a pain response was recorded as a competing risk. The independent variables were 11 a priori selected potential predictors with clinical relevance.
Of 302 analyzable patients, 262 (87%) had solid and 40 (13%) had hematologic tumors. The median total radiation dose was 30 Gy (range, 6-70.4 Gy). The pain response rate was 52% for 264 (87%) evaluable patients at 1-, 57% for 228 (75%) such patients at 2-, and 58% for 182 (60%) evaluable patients at 3-month follow-up. At 2-month follow-up, responders experienced a greater decrease in all 7 pain interference subscales of the Brief Pain Inventory compared to nonresponders. Multivariable analysis demonstrated that hematologic tumors (hazard ratio [HR], 1.85; 95% confidence interval [CI], 1.15-2.98), a neuropathic component of the index pain (HR, 1.50; 95% CI, 1.05-2.14), and opioid analgesic use before RT (HR, 0.65; 95% CI, 0.47-0.91) were independent significant predictors of pain response.
Patients with hematologic tumors, a neuropathic component of the index pain, and no treatment with opioid analgesics before RT were more likely to experience pain palliation after RT.

View all citing articles on Scopus

^☆: Part of this report was presented at the 56th Annual Meeting of the American Society of Therapeutic Radiology and Oncology in San Francisco, CA, USA, 2–6 October 2014, and at the 15th International Congress of Radiation Research, Kyoto, Japan, 25–29 May 2015.

View full text

Original ArticleNeuropathic Pain Features in Patients with Bone Metastases☆

Highlights

Abstract

Aims

Materials and methods

Results

Conclusions

Introduction

Section snippets

Materials and Methods

Results

Discussion

Acknowledgements

Clin Oncol (R Coll Radiol)

Radiother Oncol

Radiother Oncol

Radiother Oncol

Radiother Oncol

Int J Radiat Oncol Biol Phys

Radiother Oncol

Lancet Neurol

J Pain

Pain

Radiother Oncol

Original Article
Neuropathic Pain Features in Patients with Bone Metastases☆