https://orcid.org/0000-0003-4827-1961
Abstract
Background
Cervical radiculopathy occurs when a nerve root is compressed in the spine, if symptoms fail to resolve after 6 weeks surgery may be indicated. Anterior Cervical Discectomy (ACD) is the commonest procedure, Posterior Cervical Foraminotomy (PCF) is an alternative that avoids the risk of damage to anterior neck structures. This prospective, Phase III, UK multicentre, open, individually randomised controlled trial was performed to determine whether PCF is superior to ACD in terms of improving clinical outcome as measured by the Neck Disability Index (NDI) 52 weeks post–surgery.
Method
Following consent to participate and collection of baseline data, subjects with cervical brachialgia were randomised to ACD or PCF in a 1:1 ratio on the day of surgery. Clinical outcomes were assessed on day 1 and patient reported outcomes on day 1 and weeks 6, 12, 26, 39 and 52 post-operation. A total of 252 participants were planned to be randomised. Statistical analysis was limited to descriptive statistics. Health economic outcomes were also described.
Results
The trial was closed early (n = 23). Compared to baseline, the median (interquartile range (IQR)) NDI score at 52 weeks reduced from 44.0 (36.0, 62.0) to 25.3 (20.0, 42.0) in the PCF group and increased from 35.6 (34.0, 44.0) to 45.0 (20.0, 57.0) in the ACD group. ACD may be associated with more swallowing, voice and other complications and was more expensive; neck and arm pain scores were similar.
Conclusions
The trial was closed early, therefore no definitive conclusions on clinical or cost-effectiveness could be made.
Introduction
Cervical radiculopathy occurs when a nerve root is compressed in the cervical spinal canal or neural foramen, usually by an osteophyte or soft disc. This causes neck pain and radiating pain into the arm (brachialgia). Cervical brachialgia is extremely common (1.79 cases/1000 per year) and debilitating, predominantly affecting people aged 40–60 years old with up to 15% of patients unable to work due to pain.Citation1 In a large registry study (1809 patients), patients had significantly worse scores than the general population in all 8 SF-36 quality of life dimensions.Citation2
In most patients, symptoms are self-resolving with conservative management (analgesia and physiotherapy) however 26% of patients undergo surgery if their symptoms are persistent or remain debilitating.Citation3 In patients with symptoms that have failed to resolve after 6 weeks, surgical treatment is associated with a more rapid recovery than further conservative management.Citation4
The current standard operation is Anterior Cervical Discectomy (ACD), which is effective but the high incidence of significant, potentially permanent complications including dysphagia (9.5%) and hoarse voice (3.1%)Citation5 can be devastating and the high rates of repeat surgery at other neck sites (25.6% risk in 10 years)Citation6 can prevent complete recovery. Posterior Cervical Foraminotomy (PCF) is an alternative that may avoid these risks but there is a historical belief that PCF results in high levels of neck pain, spasms and the need for revision surgery.Citation7 Several non-randomised studies have suggested PCF clinical outcomes are similarCitation8–11 or better,Citation12–14 that it has lower complication rates overall compared to ACDCitation8,Citation12,Citation15 and that it is cheaper.Citation9,Citation14 Two randomised controlled trials comparing ACD with endoscopic (minimally-invasive) PCFCitation16,Citation17 have demonstrated equivalent surgical outcomes. In a systematic reviewCitation18 no difference was found between PCF and ACD in the treatment of brachialgia, with no increased complication or re-operation rates and a recent met analysis has shown no significant differences in effective rate, total complication rate and reoperations between endoscopic PCF and ACD with fusion.Citation19
Materials and methods
The primary objective was to determine whether PCF is superior to ACD in terms of improving clinical outcome as measured by the Neck Disability Index (NDI) at 52 weeks post–operation in patients experiencing symptomatic unilateral cervical brachialgia for at least six weeks, with confirmed nerve root compression on MRI imaging or CT myelogram.
Secondary objectives were to compare the two surgical procedures in terms of NDI score, neck and upper limb pain, dysphagia, globus, hoarse voice symptoms, incidence of revision surgery and cost-effectiveness over 52 weeks post-operation. Further secondary objectives were to compare the extent and severity of spinal cord functional impairment and the incidence of surgical complications in the first 6 weeks post-operation.
Exploratory objectives were to explore the impact of using a plate during ACD and minimal access during PCF on NDI and EQ-5D-3L.
Design
FORVAD was a UK multicentre, Phase III, parallel group, open, individually randomised controlled trial designed to test the null hypothesis that PCF is not superior to ACD in terms of improving clinical outcome as measured by the Neck Disability Index (NDI) 52 weeks post-surgery.
Participants were randomised (1:1) to receive PCF or ACD using a central automated service provided by Leeds CTRU. Allocation sequence was generated via minimisation incorporating a random element, with minimisation factors of centre, duration of upper limb symptoms, and smoking status. Participants were followed up in the clinic at Day 1 and 6 weeks post-operation and by post at 12, 26, 39, and 52 weeks post-operation. demonstrates the schedule of assessments.
Table 2. Data collection tools and schedule.
Patient population and setting
Patients were eligible to participate if they had been diagnosed with unilateral cervical brachialgia that had persisted for at least six weeks, resultant from single-level nerve entrapment, and had previously failed conservative management. Patients with cervical myelopathy, spinal cord compression, or who had previously had cervical spine surgery were excluded. The full eligibility criteria are provided in .
Table 1. Trial inclusion and exclusion criteria.
A registration phase allowed participants to be registered up to 28 days before their planned surgery date, to allow sufficient time for the trial baseline assessments to be conducted ahead of the participant’s operation.
Participating surgeons were invited to contribute if they were able to perform both trial procedures, had performed a minimum of ten of each surgical procedure as the primary surgeon and completed a bespoke training package on the e-brain platform (www.ebrain.net).
Interventions
Pre-operative investigations and preparation were as per individual site protocol. Participants received either PCF or ACD according to standard techniques. Minimal and open access techniques were permitted for PCF operations. For ACD operations, the choice of fusion material and the decision to use a plate were left to the surgeon discretion. Post-operative care was also as per individual site protocol.
Outcome measures
The primary outcome measure was the patient-reported percentage NDI score at 52 weeks post-operation. Secondary patient-reported outcomes, collected at baseline, day one and six, 12, 26, 39 and 52 weeks post-operation, included the numerical rating scale-neck pain, numerical rating scale-upper limb pain scales and the validated PainDETECT,Citation21 Eating Assessment Tool,Citation22 Glasgow Edinburgh Throat ScaleCitation23 and Voice Handicap IndexCitation24 tools. Secondary clinical outcomes included a restricted version of the American Spinal Injury Association assessment scale, intra- and post-operative complications, the incidence of re-operations within 52 weeks of operation, and assessment of hoarse voice from additional voice recordings collected from 25% of participants (randomly selected using a computerised algorithm) using the Grade, Roughness, Breathiness, Asthenia and Strain scoring system. Exploratory outcomes included whether participants receiving PCF received minimal or open access surgery, and whether participants receiving ACD received surgery with or without a plate. Health resource use measures, including the patient-reported EQ-5D-3L, were collected to inform cost-effectiveness.
Sample size
A total of 252 participants (126 per trial arm) were required to have 90% power to detect the minimum clinically important difference of 10% (five points) in the change in Neck Disability Index score at 52 weeks post-operation, assuming a between-patient standard deviation of 23 units,Citation12 two-sided 5% significance level and 10% loss to follow-up.
Results
Due to slower than expected accrual, funding was withdrawn and the trial closed to recruitment after randomising 23 participants, 14 to PCF and 9 to ACD, from 11 sites. 251 patients were screened for eligibility, 224 were excluded during screening including 207 who did not meet the inclusion criteria and 16 who declined to participate (). The main reasons for failing to meet the eligibility criteria were a diagnosis of cervical myelopathy (n = 38), no single-level nerve entrapment (n = 34), and no diagnosis of unilateral cervical brachialgia as confirmed by MRI or CT myelogram taken within the last 12 months (n = 30).
Figure 1. CONSORT diagram.
Baseline characteristics
The mean age was 54.0 years (SD 8.1 years; range 34–70 years). A total of 15 patients (62.5%) were female and the ethnic background of all trial participants was white. Further details of the baseline characteristics are summarised in and .
Table 3. Summary of minimisation factors at baseline by treatment group.
Table 4. Summary of participant characteristics at baseline in each treatment group.
Functional outcomes
Primary outcome measure: The median (interquartile range (IQR)) NDI reduced (improved) from: 44.0 (36.0, 62.0) to 25.3 (20.0, 42.0) in the PCF group by 52 weeks post-operation but increased (deteriorated) from 35.6 (34.0, 44.0) to 45.0 (20.0, 57.0) in the ACD group. summarises the NDI over 52 weeks. Spinal Injury Association (ASIA) score: All subjects had a total motor score of at least 98 on day 1 and a score of 99 at week 6.
Figure 2. Box plot of percentage NDI score at each time point, by treatment group.
Pain outcomes
In both groups median (IQR) arm pain score reduced (improved) on day one post-operation from 7.0 (4.0, 8.0) at baseline to 3.0 (2.0, 8.0) in the PCF group and 6.0 (5.0, 7.0) to 4.0 (0.5, 5.0) in the ACD group. Median arm pain scores reached their lowest (best) level 12 weeks post-operation in both groups, thereafter the pain scores increased (deteriorated) but remained below baseline, with median (IQR) of 5.0 (2.0, 7.0) in the PCF group and 5.0 (3.0, 6.0) in the ACD group at 52 weeks ().
Figure 3. Box plot of NRS Upper limb pain score at each time point, by treatment group.
With regards to neck pain, there was an initial increase from baseline in median (IQR) score on day one post-operation in both groups 5.5 (4.0, 8.0) at baseline to 8.5 (6.0, 10.0) in the PCF group and 5.0 (4.0, 7.0) at baseline to 7.0 (4.0, 9.0) in the ACD group. Thereafter neck pain decreased in both treatment groups; at 52 weeks, median (IQR) scores were 4.0 (2.0, 5.0) in the PCF group and 5.0 (3.0, 7.0) in the ACD group.
PainDETECT category scores fluctuate over the post-operative period in the PCF group but reduce over time in the ACD group suggesting that a higher proportion of patients had developed nociceptive rather than neuropathic pain in the ACD group.
Swallowing and hoarse voice
Generally the Glasgow Edinburgh Throat Score (GETS) scores were observed to be higher (worse) in the ACD group over 52 weeks whereby the median (IQR) score increased (deteriorated) from 0.0 (0.0, 3.0) at baseline to 15.0 (10.0, 25.0) at day 1 post-operation, whereas in the PCF group the median (IQR) score increased (deteriorated) from 0.0 (0.0, 6.0) at baseline to 3.0 (1.0, 10.0) at day 1. By week 52 the median (IQR) scores were 2.5 (2.0, 5.0) and 0.0 (0.0, 8.0) for ACD and PCF respectively.
The day 1 post-operative median (IQR) Eating Assessment Tool-10 score was higher (worse) in the ACD group (13.5 (3.5, 16.0)) than in PCF (0.0 (0.0, 4.0)) but this observed difference resolved by 12 weeks and was maintained at 52 weeks (median (IQR) of 0.0 (0.0, 1.0) and 0.0 (0.0, 6.0) at 52 weeks in the ACD and PCF groups respectively).
The median (IQR) Voice Handicap Index score was lower (better) in the PCF group (0.0 (0.0, 2.0)) than the ACD group (2.0 (0.5, 8.5)) on day 1 post-operation, after which the two groups were comparable.
A total of 8 voice recordings were obtained from 5 literate participants. Across all voice recordings, no participants were judged to experience more than a mild degree of issues, and this did not change between baseline and six weeks post-operation.
Other outcomes
Five post-operative complications were reported in five participants, all occurring in the ACD group within 6 weeks post-operation. Reported complications included two instances of dysphagia, a “wound infection”, “urinary retention”, and “wound redness stitches overtight”. No serious or unexpected serious complications, deaths or re-operations were reported.
Health economics
Median healthcare costs of the initial surgery, including devices, operation (including tests and medications and equipment and supplies), and hospital stay, were £2,622 (interquartile range: £2,402, £2,824) in the PCF group (n = 12) and £4,423 (Interquartile range £3,849, £4,821) in the ACD group (n = 8). These costs were driven by the time in theatre, which was a median 45 minutes shorter with PCF (median 0.87, interquartile range: 0.81-1.00) than ACD (median 1.66, interquartile range: 1.25–1.81).
The median costs from the NHS & Personal social services perspective at 6 weeks after randomisation were £2634 (IQR: 2444 to 2741; missing 3 of n = 9) in the PCF arm and £4214 (IQR: 3602 to 4994; missing 6 of n = 14) in the ACD arm. Costs from a societal perspective were also calculated, which included patients’ out-of-pocket costs and productivity losses from time taken off work due to their surgery or complications in addition to NHS and social care service costs. Median per patient costs to society at 6 weeks were £4097 (IQR: 2448 to 6591; missing 7 of n = 14) in the PCF arm and £4143 (IQR: 4126 to 4284; missing 4 of n = 9) in the ACD arm. Results including resource use after 6 weeks are not presented due to high attrition, which left no patients in the ACD arm with complete data for analysis.
There were more frequent reports of severe problems with anxiety and depression and more severity of Pain and Discomfort in the EQ-5D-3L classification system for PCF than ACD at baseline, resulting in median utility scores of 0.210 (IQR −0.01 to 0.60) and 0.689 (IQR: 0.66 to 0.69) respectively. This is likely to have played a role in the larger observed gains from baseline in post-operative EQ-5D sores for patients in the former than the latter trial group (median change at 6 weeks 0.10 (IQR 0.00 to 0.13, missing 5 of n = 14) and 0.02 (IQR −0.03 to 0.06, missing 1 of n = 9) respectively).
Discussion
Due to slow recruitment, the trial funding was withdrawn by NIHR at the start of the COVID-19 pandemic; investigators decided not to contest the decision as recruitment through the COVID pandemic was predicted to be challenging. The trial was therefore underpowered and definitive conclusions on clinical and cost effectiveness could not be made.
Despite its small size this trial does provide some evidence to support that PCF may be associated with better outcomes; NDI at 52 weeks improved in the PCF group but deteriorated in the ACD group, all five surgical complications were seen in ACD patients and PCF was around 40% cheaper.
The slow recruitment to this trial appeared to be due to human factors and the trial design including the long lag time between referral and an operation, the lack of individual equipoise and concern about randomisation on the day of surgery. A formal qualitative analysis has been undertaken and will be published separately. A recent article has shown that nearly a quarter of all trials in spinal surgery had not been completed and half were unpublished and that under-reporting of spinal clinical trials can distort the evidence landscape.Citation25
251 patients were screened but only 27 (10.7%) were deemed eligible. Patient refusal to participate was only a small factor (16/251, 6.4%); most (208/251, 82.8%) were excluded because they did not meet the inclusion criteria. Centre recruitment to screening ratios varied from 1:5.8 to 0:1, which appears to be due to local variations in how patients were identified and different degrees of individual equipoise. The centre that recruited the most participants was also the centre that initiated the trial, high recruitment rates were achieved in this centre by triaging referrals of patients with suitable MRI scans to a dedicated research clinic. This method is recommended in any future trials.
To minimise bias, the trial incorporated randomisation on the day of surgery. Unfortunately, a recent spinal legal case in the UK concluded that a patient should not be given any new information on the day of surgery and this has resulted in a move away from consent for surgery on the day.Citation26 Whilst fully informed consent to participate in the trial including consent to either operation was obtained well in advance, randomisation on the day was felt by some surgeons to be legally difficult and this contributed to low recruitment rates in some centres. Future trial protocols should avoid randomisation on the day of surgery for this reason.
Conclusions
The trial provides an indication that PCF may be associated with better outcomes, with fewer complications and potentially less cost than ACD. NDI at 52 weeks improved in the PCF group but deteriorated in the ACD group; all five surgical complications were seen in ACD patients and PCF was around 40% cheaper. However, as the trial was closed early, with the small sample size no definitive conclusions can be made.
A large multicentre randomised controlled trial comparing ACD and PCF in the treatment of cervical brachialgia is still required and would provide us with interesting and useful data. Future investigators should incorporate the lessons learned from this trial in future trial designs.
Ethical approval
Regional Ethics Committee approval (REC): 18/NW/0682
Copyright materials
Copyright release permission for all copyrighted materials have been obtained and will be provided to the publisher.
International standard randomised controlled trial number
ISRCTN reference: 10133661
Level of Evidence
Level 2 using OCEBM Levels of Evidence Working Group*. The Oxford 2011 Levels of Evidence. Oxford Centre for Evidence-Based Medicine. http://www.cebm.net/index.aspx?o=5653
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
Data supporting this study are available from the Clinical Trials Unit of the University of Leeds. Access to the data is subject to approval and a data-sharing agreement due to patient confidentiality.
Additional information
Funding
References
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