Background Cordotomy can be effective in relieving pain for patients with mesothelioma, but the evidence to support continued provision is limited. This review forms part of the Invasive Neurodestructive Procedures in Cancer Pain pilot study: The role of cordotomy in mesothelioma-related pain in the UK.
Aim/design We report on the results of the first comprehensive systematic review of the use of cordotomy in mesothelioma-related pain, with specific reference to effectiveness in relieving pain and safety. The review was conducted according to guidelines reported in the NHS Centre for Reviews and Dissemination and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic reviews and meta-analyses.
Data sources 14 databases from inception to March 2012 were searched, with no limitations on language or publication type.
Results Nine studies met the inclusion criteria, all of which were case series of percutaneous cervical cordotomy (PCC) involving 160 patients. All studies demonstrated good pain relief in the majority of patients. Initial post-procedure measurements showed the greatest reduction in pain. Some side effects (headache, mirror pain, motor weakness) occurred relatively frequently but were mostly transient. Respiratory dysfunction post-PCC was rare. No deaths were directly ascribed to cordotomy.
Conclusions The available evidence is significantly limited in quantity and quality. Although it seems to suggest that cordotomy might be safe and effective in this setting, more reliable evidence is needed to aid decision making on continued provision. A national registry for cordotomy would be a valuable first step in this process.
- systematic review
- palliative care
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In the UK in 2008, 2400 people were diagnosed with mesothelioma.1 The incidence is still rising and is expected to peak around 2020.1 ,2 More patients die of mesothelioma than cervical cancer, malignant melanoma or endometrial carcinoma.3 Between 2006 and 2020, up to 30 000 people will die of mesothelioma in the UK.3 Palliative care and symptom control is central to the management of patients as the disease is often associated with difficult pain syndromes and other symptoms that may respond inadequately to pharmacological approaches alone. The National Mesothelioma Framework suggested that patients should have access to services that offer cordotomy as a palliative intervention to provide relief from challenging pain syndromes.4 However, great inequity exists in the provision of services offering cordotomy; new services are being established, while others have closed (Makin, unpublished data, 2012). For a small group of patients the procedure may yield significant analgesic benefit, yet there is an unquantified associated morbidity.
There seems to be little published evidence to support continued provision and commissioning of cordotomy, a fact that is supported by the findings of Raslan et al5 who concluded that ‘evidence needs to meet the current evidence-based standards through clinical trials.’ In an attempt to consolidate all available evidence, the Invasive Neurodestructive Procedures in Cancer Pain (INPiC) pilot study was designed to focus on the use of cordotomy in mesothelioma-related pain (Makin, unpublished data, 2012). This review was conducted as part of the INPiC pilot study. This article reports on the results of the first comprehensive systematic literature review, with specific reference to safety and effectiveness of cordotomy in mesothelioma-related pain.
This systematic review was conducted and reported according to NHS Centre for Reviews and Dissemination (CRD) Report 47 and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.6 ,7 A preliminary scoping search showed a limited evidence base; the search strategy was therefore designed for sensitivity rather than specificity. A search strategy developed for Medline was adapted for 13 other databases; all were searched from inception until March 2012 (table 1). Reference lists from previous reviews and included studies were hand searched.
Inclusion criteria were as follows:
Participants: patients with mesothelioma where the intention was to perform cordotomy (open or percutaneous) as a treatment for the control of intractable pain.
Intervention: cordotomy: the creation of a permanent (often heat created by radiofrequency technique) lesion in the lateral spinothalamic tract in the anterolateral spinal cord.
Control: treatment for pain using other modalities (pharmacotherapy or other neuroinvasive or neuroablative procedures).
Outcomes: effectiveness in relieving pain and side effects.
Study design: any, except reviews and single case reports.
There were no limits on language, year of publication or publication status. Two reviewers independently screened the titles and abstracts for relevancy. Disagreements were resolved by discussion or, if necessary, a third reviewer.
In studies that reported data on multiple diseases (including mesothelioma), only information relevant to mesothelioma was extracted. In studies where this was not possible (n=11), we wrote to the corresponding author and asked if they could supply us with separate data for mesothelioma patients.8–18 One author forwarded individual patient data.14
Quality assessment was performed using criteria based on the CRD quality assessment guideline for case series.19 Data were extracted into predesigned forms.
Data were described using a narrative synthesis. As sample sizes of included studies were small and data potentially skewed, results were reported as median plus IQR. There were insufficient studies to assess the possibility of publication bias by funnel plots or related statistics. Outcomes were evaluated according to four follow-up periods: immediately post-procedure until 2 days, at 2 weeks, at 28 days and more than 28 days.
We included data on all patients where the intention was to perform cordotomy, meaning the patients went to theatre to have the procedure, whether they actually had a permanent (heat) lesion created or not.
The findings for ‘overall pain relief at up to 2 days post-procedure’ were pooled to produce a weighted average effect (meta-analysis). The analysis using a fixed-effect model (inverse-variance weighted method)20 resulted in heterogeneity and therefore a random-effects model (DerSimonian and Laird) was also used. The analysis was consolidated using Stata V.9 and with pooled estimates of log odds converted to probability (or risk) of complete pain relief.
Results of systematic review
The results are presented under the following headings:
Study characteristics (see online supplementary table S1)
Quality assessment (⇓table 3)
Synthesis of reported outcomes (see online supplementary table S2)
The results of the literature searches are illustrated in figure 1. An overview of the nine studies that met the inclusion criteria is listed in online supplementary table S1. All the studies were case series recorded between 1983 and 2011 involving a total of 160 participants (sample size ranging from 3 to 53)21 ,22(Antrobus, unpublished data, 2011). Follow-up times ranged from 24 h post-procedure to 6 months or until death (table 2). All studies were in secondary care settings. Five of the included studies were prospective14 ,17 ,23 ,24 (Sharma, unpublished data, 2011), three were retrospective22 ,25 (Antrobus, unpublished data, 2011) and one study may have been prospective, but this remains unclear.21 Two studies were unpublished (Antrobus, unpublished data, 2011, Sharma, unpublished data, 2011) (see online supplementary table S1).
Participants were adults where the intention was to perform percutaneous cervical cordotomy (PCC) as a treatment for the control of severe or intractable pain due to mesothelioma (see online supplementary table S1). All studies reported on the maximum intended follow-up after the procedure (range 2–365 days). Only Jackson et al22 reported detailed information regarding the stage of the disease (Butchart26 Stage 2 or above, or Tumour Node Metastasis (TNM)27 Stage 4). All studies, except Sharma (2011), reported age of participants (range 18–89 years). Six studies reported gender involving a total of 107 participants, 80/107 (74.77%) were men and 27/107 (25.23%) women14 ,21–24 (Antrobus, unpublished data, 2011).
Pre-procedure pain descriptors were reported under four headings: site of pain, nature/type of pain, pain intensity (score) and analgesia use. All nine included studies stated that the pain was unilateral. Six studies explained more about the nature or type of pain14 ,17 ,22 ,23 ,25 (Sharma, unpublished data, 2011). Three stated that pain was ‘intractable’17 ,22 ,23 with Jackson et al22 adding that pain was typical of chest wall involvement. Raslan(a) described pain as somatic or visceral,14 Sharma (2011) as nociceptive or mixed and Crul et al25 as either ‘continuous somatic’, ‘continuous visceral’, ‘continuous neuropathic’ or ‘incident neuropathic’.
Six studies reported on pre-procedure pain intensity. Five used 11 point scales (patient self-report measures of pain ranging from no pain=0 to worst pain ever=10). Three of these reported a median pre-procedure pain intensity score which ranged from 7.5 to 9.14 ,24 ,25 The other two reported a score for the maximum and average pain experienced in a pre-procedure interval: Antrobus (2011) noted pain during the last week (worst: median=10, average: median=7) and Sharma (2011) reported pain in last 24 h (maximum: mean=8.71, average: mean=6.76). Nicosia et al21 and Raslan(a) reported a median pain score of four on their respective five-point scales.14
Pre-procedure analgesic and opioid use was recorded in five studies23 ,25 (Antrobus, unpublished data, 2011, Sharma, unpublished data, 2011), and three reported on coanalgesic use22 ,25 (Antrobus, unpublished data, 2011). Almost all patients were on strong opioids (range 98.11% to 100%)22 ,23 ,25 (Antrobus, unpublished data, 2011, Sharma, unpublished data, 2011), with doses reported in three studies (in morphine equivalents over 24 h) as median=410 mg,25 median=100 mg22 and mean=153.13 mg (Sharma, unpublished data, 2011). Coanalgesic use: Crul et al25 noted that some patients were on neuropathic agents and Jackson et al22 reported that 36 patients (36/53,67.92%) were on morphine and coanalgesics.
Four studies used likely prognosis as one of their inclusion criteria, although none specified the criteria used to estimate prognosis14 ,21 (Antrobus, unpublished data, 2011, Sharma, unpublished data, 2011). Survival post-procedure was recorded in four studies (range 227–36 527 days) 17 ,22 ,25 (Antrobus, unpublished data, 2011).
Five studies reported performance status: four14 ,21 ,23 ,25 used the Karnofsky Performance Status (KPS) Scale, where 100 is perfect health and 0 is death (median ranged from 55 to 75)14 ,25 and one (Antrobus, unpublished data, 2011) the Brief Pain Inventory for interference in aspects of daily life (general activity median=9). Three studies gave descriptors of respiratory function.17 ,23 ,25
All studies reported on PCC and none on open cordotomy. Six used X-ray control17 ,21 ,22 ,25 (Antrobus, unpublished data, 2011, Sharma, unpublished data, 2011) employing the standard Lipton technique (with cervical vertebrae [C]1/2 foramen entry, lateral approach).28 Two studies used water-soluble contrast,17 ,22 while others used lipid-soluble contrast. Although there were differences in the starting temperature and duration, all authors titrated the heating of the cordotomy probe to an observed effect on pain relief or sensory examination. Sedation in small doses was used in some of the studies. Three studies used CT guidance.14 ,23 ,24 Raslan(b), in his 2005 study, employed an anterior transdiscal approach at C4/5 or C5/6 level using water-soluble contrast.24 Four studies reported on staff performing or assisting in the procedure14 ,24 (Antrobus, unpublished data, 2011, Sharma, unpublished data, 2011). All procedures were performed by a pain specialist assisted by others, including a radiographer and theatre support staff (Antrobus, unpublished data, 2011, Sharma, unpublished data, 2011). Five patients in three studies did not have heat lesions due to needle or electrode placement difficulties17 ,24 (Antrobus, unpublished data, 2011).
Based on the quality assessment presented in table 3, the reviewers felt equal importance could be assigned to the evidence in the included studies as all had one or more limitations: loss to follow-up of more than 10%17 ,23 (Sharma, unpublished data, 2011), non-consecutive series,22 retrospective22 ,25 (Antrobus, unpublished data, 2011), more than 20 years old21 and included less than 10 patients21 ,24 ,25 (Antrobus, unpublished data, 2011).
Synthesis of reported outcomes
Effectiveness of cordotomy for pain relief
The reported outcomes are presented under the following headings (see online supplementary table S2):
Overall pain relief (table 4)
Analgesic level (dermatomal)
Total sleeping hours
Patient satisfaction (see online supplementary table S2)
Overall pain relief
Outcomes in six studies could be grouped into complete, partial or poor pain relief14 ,17 ,21 ,23 ,24 (Antrobus, unpublished data, 2011). Complete pain relief (‘complete’ or ‘pain free’ or ‘no pain’) was attained in 80.22% (73/91) of patients where the intention was to perform PCC. In patients who actually received a heat lesion, complete pain relief was recorded in 84.88% (73/86). Partial pain relief (‘partial’ or ‘partial satisfactory’ or ‘initial or satisfactory’ or ‘significant’) was achieved in 14.29% (13/91) where PCC was intended (vs heat lesion 13.95% [12/86]). Poor pain relief (‘poor’ or ‘none’) was reported in 5.49% (5/91) (heat lesion 1.16% [1/86]). Most patients were still on some form of oral analgesia post-procedure (see online supplementary table S2), so that ‘overall pain relief’ reflected patients’ views on the effectiveness of their full analgesic regimen.
These six studies were included in the meta-analysis (table 4), where the ordinal data were dichotomised to complete versus partial/poor pain relief14 ,17 ,21 ,23 ,24 (Antrobus, unpublished data, 2011). In patients where PCC was intended (n=91), the proportion with complete pain relief ranged from 20% to 100%, with a weighted average of 75% based on a random-effects model (95% CI=52% to 89%). There was a moderate level of between-study heterogeneity (I2=57%) which appeared to be affected by two studies that had small sample sizes and event rates24 (Antrobus, unpublished data, 2011). In patients who had heat lesions (n=86), the proportion with complete pain relief ranged from 33% to 100%, with a weighted average of 83% based on a fixed-effect model (95% CI=72% to 90%; I2=32%).
The seventh study reported pain data on a continuous scale which could not be dichotomised (Sharma, unpublished data, 2011).
At 2 weeks’ follow-up, Raslan(b) reported that three patients (3/5,60%) continued to have satisfactory to complete pain relief.24
Two studies reported on overall pain relief at 28 days post-procedure. Raslan(a) noted that 23 patients (23/24,95.83%) had pain relief, of whom 20 (83.33%) had complete pain relief.14 Sharma (2011) reported a mean of 4.45 (4='about the same’ to 5='slightly better’) on their seven-point ‘Global Impression of Change Scale’.
At more than 28 days follow-up, Kanpolat et al23 stated that 13 patients (13/13, 100%) were recorded as being pain free after an average follow-up period of 5.9 months and in Nicosia et al21 three (3/3, 100%) had complete pain relief at an average of 3 months follow-up. Raslan(a) reported that at 3 months follow-up 23 patients (23/24, 95.83%) had pain relief, of which 17 (70.83%) experienced complete pain relief, and that at 6 months follow-up 22 (22/24, 91.67%) had pain relief, of which eight patients (33.33%) had complete pain relief.14
Four studies reported on this outcome using either the Numerical Rating Scale (NRS) or Visual Analogue Scale (VAS) 14 ,24 ,25 (Sharma, unpublished data, 2011). All studies reported an improvement immediately post-procedure. In three the median score ranged from zero to three (vs median pre-procedure range of 7.5–9).14 ,24 ,25 The remaining study reported an average pain relief score of 0.52 in the last 24 h and a maximum of 0.52 (vs pre-procedure average score of 6.76 and a maximum of 8.71) (Sharma, unpublished data, 2011).
At 2 weeks’ follow-up, Raslan(b) reported a mean NRS score of 3.1.24 At 28 days, Raslan(a) noted a median overall VAS score of two.14 Sharma (2011) reported an average pain relief score of two in last 24 h and a maximum of 2.16.
Analgesic interventions (including oral analgesic use and invasive procedures for pain management)
Post-procedure opioid doses were reported in two studies. In Crul et al25 the median dose of morphine was 120 mg (vs pre-procedure 410 mg) and Jackson et al22 reported the lowest daily dose as a median of 20 mg (vs pre-procedure 100 mg). Price et al17 stated that ‘opioid dose was halved following successful PCC ‘.Jackson et al22 reported that 43 patients (43/52, 82.69%) had more than 50% reduction in opioid dose, and 20 (20/52, 38.46%) stopped taking opioids altogether. Antrobus (2011) described the reduction as ‘significant’ with one patient (1/3,33.33%) requiring ‘fewer interval doses in the first 24 h’ and another (1/3, 33.33%) developed opioid toxicity immediately post-procedure. In the Crul et al25 study one patient (1/4, 25%) needed an increase in opioid dose post-procedure.
At 2 weeks’ follow-up, Raslan(b) reported ‘stabilization of […] pain medication dosages or even reduction of the dose’, but didn't specify the number of patients in whom this was the case.24 In the Jackson et al22 study, 18 patients (18/52, 34.62%) had recurrence of pain requiring increase in opioid dose after median of 9 weeks (range 0.71–26). Nicosia et al21 reported that two patients (2/3, 66%) required additional oral or intramuscular morphine to reach complete pain relief at an average follow-up of 3 months.
Two other studies commented on opioid use, but did not specify clear time points of follow-up. Kanpolat et al23 stated that ‘in cases receiving opioid medication, doses of the drug were slowly decreased, and none of the cases received opioid treatment in their follow-up’. Sharma (2011) reported a mean percentage reduction in opioid use of 53.57% (data on 14 patients).
Two papers reported coanalgesic use: Crul et al25 stated that ‘in virtually all cases non-opioids such as acetaminophen and NSAIDS were continued following successful PCC’ and Jackson et al22 stated that 18 patients (18/53, 33.96%) continued on coanalgesics (vs pre-procedure 67.92%).
Analgesic level (dermatomal)
Immediately post-procedure, Kanpolat et al23 noted that 15 patients (15/19, 78.95%) had selective pain relief (ie, segmental block) and in four patients (4/19, 21.05%) the block involved all segments below the highest level of anaesthesia. Price et al17 stated that the maximum height of the blockade at 24 h ranged from C3 to T1 dermatome. This remained the same at 2 weeks. Raslan(b) reported that all three patients who had heat lesions had a recorded level of anaesthesia at T1 dermatome at 2 weeks’ follow-up.24
Total sleeping hours
In one study, patients’ sleeping time showed an improvement immediately post-procedure (median of seven vs pre-procedure median of three), although this did decrease over the follow-up period (6 months median of five).14
Sharma (2011) reported data on 14 patients (14/17, 82.35%) at 2 days post-PCC. All 14 said it had been worthwhile having the procedure. At 28 days, eight patients (8/9, 88.89%) felt it was worthwhile.
The reported outcomes are presented under the following headings (table 5):
Deaths following the procedure
All included studies detailed procedure-specific adverse events, noting either events that occurred (some specifying the duration of impairment) or potentially significant adverse events that did not occur.
Motor weakness: Two studies14 (Antrobus, unpublished data, 2011) (44 patients) noted no patients with weakness or change in motor power but in four studies neurological deficit was recorded in 15 patients (15/127, 11.81%)17 ,21 ,22 (Sharma, unpublished data, 2011). Deficit was described as ‘persistent motor weakness’, ‘transient ipsilateral leg weakness’, ‘transient weakness-ataxia’ and ‘nerve damage’.
Mirror pain: Crul et al25 reported transient mirror pain in one patient (1/4, 25%). Sharma (2011) noted mirror pain in three patients (3/17, 17.65%) at 2 days post-procedure, and in two patients (2/17, 11.76%) at 28 days.
Urinary dysfunction/impotence: Jackson et al22 reported no incontinence due to sphincter disturbance and no impotence in 53 patients post-PCC. Nicosia et al21 noted short-lived urine retention in one case (1/20, 5%), which resolved after repeated catheterisations.
Headaches: Two studies described transient headaches in 13 patients (13/58, 22.41%)14 (Sharma, unpublished data, 2011).
Price et al17 noted short-lived confusion in three patients (3/35, 8.57%) and one patient (1/35, 2.86%) with worsening left ventricular failure following a blood transfusion. Jackson et al22 reported chest infection with pyrexia in two patients (2/53, 3.77%).
Our review found the evidence base for the use of PCC in mesothelioma-related pain to be small. All the included studies reported case series where unilateral PCC was offered for patients suffering intractable pain due to mesothelioma. Although multiple techniques were described to perform PCC, X-ray guided techniques were most commonly used. The studies used different measures to describe effectiveness of the procedure.
All nine case series demonstrated good pain relief in the majority of patients. This was derived from using overall pain relief measures, pain intensity scores, opioid use and dermatomal analgesic levels. Initial post-procedure measurements showed the most effect, and although the improvement in pain levels tended to lessen over time, it did not revert to pre-procedure levels. Other outcome measures also showed beneficial effect, including increased performance status and increased total sleeping hours. The majority of patients seemed to be satisfied with the procedure. A minority of patients did not have significant benefit from the procedure and required further pain blocks or repeat cordotomy.
The included studies described a range of adverse effects. Some side effects (headache, mirror pain, motor weakness) occurred relatively frequently (more than 10% of reports) but were mostly transient. Respiratory dysfunction post-PCC was rare. A number of deaths were described within 12 months of the procedure, all attributed to disease progression rather than PCC.
Strengths and limitations
The strengths of the review lie in the fact that we conducted the first comprehensive systematic review specifically on the use of cordotomy in mesothelioma-related pain. The review was not limited by either language or publication type.
The results of the review should be regarded in the context of its significant limitations, chiefly due to the low quantity and poor quality of the available evidence. All studies were case series, which are generally placed at the bottom of the evidence hierarchy.29 ,30 ,31 The included studies either had small sample sizes, were retrospective and/or used a variety of outcome measures at different reporting intervals. Two of the studies are as yet unpublished. Also of note is that the three single author studies where all procedures were conducted by the author (who is likely to be an advocate of the procedure with high expectations of the procedure and carefully selected patients) might be seen as less reliable and generalisable than those with a reporting team.
Many of the authors of included studies described the reason for PCC as intractable or severe or uncontrolled pain, and some added more pain descriptors as well as prognostication to the criteria. The studies did not, however, all use directly comparable definitions of these criteria and hence the collated evidence did not give a clear indication of when the procedure should be considered, neither in terms of distinct pain parameters, nor the point in the disease trajectory or performance status of the patient.
The available evidence is significantly limited in quantity and quality. Although it seems to suggest that cordotomy might be a safe and effective procedure for patients with intractable pain due to mesothelioma, in isolation it does not aid the decision making on whether continued provision of cordotomy services is warranted.
There is another consideration at play—the procedure is performed by only a handful of practitioners (Makin, unpublished data, 2012) and this skill will be lost if the weight of evidence does not tip the balance in favour of continued provision. This would be devastating for the small group of patients in whom it yields significant analgesic benefit. It is therefore imperative that good quality evidence is provided soon by well-designed primary studies so that firm conclusions can be drawn on its effectiveness and safety.
A UK-wide registry for cordotomy could be the first step in achieving this. The comprehensive reporting will not only aid benchmarking and lead to improved patient outcomes but will also crystallise questions for further research. Parallel qualitative research into patient experiences would augment our understanding of the impact of the procedure.
We thank Dr Jim Turner and Dr Belal Hannan for their practical help during this research and Richard Bailey and staff at the John Spalding Library, Wrexham Medical Institute. We also thank the authors who contributed independent patient data to the review.
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Files in this Data Supplement:
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Contributors Planning: BDF, RAL and MP; literature search, quality assessment, data extraction: BDF and MP; meta-analysis: RAL; synthesis of results: BDF, MLS and MP; report writing: BDF and MP; reviewing and finalising report: BDF, RAL, MLS and MP; guarantors: BDF and MP.
Funding This study was funded as part of the INPIC pilot trial by an NCRI Lung Cancer Supportive and Palliative Care Research Grant no. LCSuPaC17 (main study £122 229 of which £25 000 was subcontracted to Cardiff University to complete the systematic review).
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.