Minimally Invasive Cordotomy for Refractory Cancer Pain: A Randomized Controlled Trial

Can a cordotomy improve pain outcomes in optimally medically treated patients with refractory cancer pain? This article addresses the question.

Abstract

Background.

Up to 30% of patients with cancer continue to suffer from pain despite aggressive supportive care. The present study aimed to determine whether cordotomy can improve cancer pain refractory to interdisciplinary palliative care.

Materials and Methods.

In this randomized controlled trial, we recruited patients with refractory unilateral somatic pain, defined as a pain intensity (PI) ≥4, after more than three palliative care evaluations. Patients were randomized to percutaneous computed tomography‐guided cordotomy or continued interdisciplinary palliative care. The primary outcome was 33% improvement in PI at 1 week after cordotomy or study enrollment as measured by the Edmonton Symptom Assessment Scale.

Results.

Sixteen patients were enrolled (nine female, median age 58 years). Six of seven patients (85.7%) randomized to cordotomy experienced >33% reduction in PI (median preprocedure PI = 7, range 6–10; 1 week after cordotomy median PI = 1, range 0–6; p = .022). Zero of nine patients randomized to palliative care achieved a 33% reduction in PI. Seven patients (77.8%) randomized to palliative care elected to undergo cordotomy after 1 week. All of these patients experienced >33% reduction in PI (median preprocedure PI = 8, range 4–10; 1 week after cordotomy median PI = 0, range 0–1; p = .022). No patients were withdrawn from the study because of adverse effects of the intervention.

Conclusion.

These data support the use of cordotomy for pain refractory to optimal palliative care. The findings of this study justify a large‐scale randomized controlled trial of percutaneous cordotomy.

Implications for Practice.

This prospective clinical trial was designed to determine the improvement in pain intensity in patients randomized to either undergo cordotomy or comprehensive palliative care for medically refractory cancer pain. This study shows that cordotomy is effective in reducing pain for medically refractory cancer pain, and these results can be used to design a large‐scale comparative randomized controlled trial that could provide the evidence needed to include cordotomy as a treatment modality in the guidelines for cancer pain management.

Introduction

More than 90% of patients with cancer develop pain that is attributable to their tumor [1]. The introduction of multimodal therapy, along with incorporation of the World Health Organization guidelines for cancer pain management, has led to a significant reduction in the burden of cancer pain [2], [3]. However, despite maximal medical therapy, up to 30% of patients with cancer continue to suffer from pain [4], [5]. In addition to the physical suffering caused by cancer pain, high pain scores are also associated with a high rate of hospital readmission and interruption in cancer therapy [6], [7].

Neurosurgical interventions for pain control have a long history and have included lesioning techniques targeting the brain (cingulotomy, thalamotomy, mesencephalotomy) and spinal cord (dorsal root entry zone lesion, cordotomy, myelotomy) [8]. These lesions were historically invasive and associated with high morbidity and lacked carefully designed trials to support their effectiveness [9]. Cordotomy is a lesion of the spinothalamic tract which may be of use for cancer pain. Although prior cordotomy techniques were associated with a high morbidity [10], [11], two recent series have shown that percutaneous computed tomography (CT)‐guided cordotomy is safe and effective for the treatment of refractory cancer pain [12], [13]. However, the role of cordotomy in the U.S. at comprehensive cancer centers is unknown, as the patients treated in prior series [12], [13] outside the U.S. did not have access to interdisciplinary treatment teams or to optimal opioid therapy. Hence, the question remains whether cordotomy can improve pain outcomes in optimally medically treated patients with refractory cancer pain.

In this study, we test the hypothesis that cordotomy improves pain intensity in carefully selected patients who have refractory pain after pharmacological and nonpharmacological management by a specialist‐driven palliative care team.

Materials and Methods

This study was approved by the Institutional Review Board at MD Anderson Cancer Center, and the clinical trial was monitored by an Institutional Data and Safety Monitoring Board.

Patient Selection

Potential participants for this study were identified from the palliative care clinic at MD Anderson Cancer Center. Appropriate candidates for cordotomy are those patients with one‐sided, somatic pain caused by tumor involvement below the shoulder level (C5 dermatome) and with a life expectancy greater than 3 months. Patients at the palliative care clinic undergo interdisciplinary treatment that includes pharmacological therapy, counseling, and physical techniques as deemed appropriate for the management of a particular patient. A patient's pain was determined to be refractory if the patient had a pain intensity ≥4 on a 0–10 numerical rating scale, after an initial consultation and at least two clinical follow‐up evaluations by the palliative care team. Upon determination that the pain is refractory, a patient who met the other study inclusion criteria above was referred to the principal investigator for consideration of study enrollment. Patients with significant pulmonary dysfunction, large intracranial metastases, significant thrombocytopenia, or coagulopathy were excluded from participation in this study. The treating neurosurgeon confirmed a patient's eligibility for cordotomy and obtained the patient's consent for the study.

Funding for this study permitted a recruitment period of 24 months, after which the study would be terminated. At the inception of this trial, percutaneous cordotomy was a relatively new intervention being offered at our institution. Hence, data characterizing the percentage of patients with refractory pain who were eligible for cordotomy were limited. As our palliative care clinic provides more than 1,000 patient consultations per year, we estimated that we could recruit 60 patients to the study over the 2‐year study period.

Study Design

In this single‐institution, nonblinded clinical trial, patients were randomized to undergo cordotomy (Group 1) or to continue with comprehensive palliative care (Group 2). Because prior pain research has shown a considerable placebo effect [14], the study was designed as a noncomparative trial aimed at determining the response rate for both the treatment and control group, with the expectation that this would inform an adequately powered future randomized controlled trial. The primary endpoint was the pain intensity 1 week after cordotomy (Group 1) or study enrollment (Group 2), as determined by the Edmonton Symptom Assessment Scale [15]. At the end of the first week, if a patient in Group 2 continued to have a pain intensity ≥4, he or she was allowed to cross over and was offered cordotomy.

In addition to face‐to‐face assessments on study days 1 and 7, patients in both Group 1 and Group 2 were contacted by phone daily to obtain daily assessments of their pain intensity. During the phone call, patients were assessed using the Edmonton Symptom Assessment Scale (ESAS) and the Brief Pain Inventory (BPI) [16]. In the longer term, patients were followed for at least 6 months on a monthly basis in the palliative care clinic for medical treatment and monthly assessments with the BPI. All patients undergoing a cordotomy underwent a thorough neurological examination before the procedure, on postoperative day 1, and on postoperative day 7 to detail any potential complications [10], [11].

Surgical Procedure

The detailed surgical technique for cordotomy has been previously published [17]. Patients for cordotomy underwent a preprocedure cervical myelogram by instillation of adequate contrast into the lumbar cistern to allow visualization of the spinal cord in the upper cervical spine. The patient was then taken to the radiology suite, where the procedure was performed. The procedure was performed using intravenous anesthesia sedation to allow interaction with the patient prior to lesion generation. Using real‐time CT guidance, a radiofrequency electrode (Cosman Medical, Burlington, MA) was guided to the anterolateral quadrant of the spinal cord at the C1–C2 level.

Once the electrode was in the radiographically optimal position, sensory and motor testing was performed at 100 Hz and at 2 Hz, respectively, with square wave pulses and a 0.1‐ms pulse duration. Stimulation was performed to ensure no motor contractions existed at a voltage <1 V, to ensure a safe distance from the corticospinal tract. Sensory stimulation was performed to ensure patients felt warmth, paresthesia, or pain in the region of the body affected by the pain at a voltage <0.5 V. This confirmed the electrode position in the spinothalamic tract physiologically.

Once ideal position of the electrode was confirmed, two or three ablations were performed at 80°C for 60 seconds. Testing was performed during the procedure to assess for the development of hypalgesia and to ensure no change in motor weakness. After the procedure, patients were transferred to recovery and admitted for 23‐hour observation.

Quantitative Sensory Testing

To assess the physiological impact of cordotomy on pain transmission, patients underwent quantitative sensory (QST) prior to cordotomy and on postprocedure days 1 and 7. The detailed QST protocol has also been published previously [18]. In brief, patients were tested to determine the threshold for detection of sharpness pain (from 8 g to 128 g) and heat pain (32°C–51.5°C) in the area of maximum pain, hand, and foot.

Outcome Metrics

A 33% improvement in pain intensity assessed using an 11‐point numerical rating scale from 0 to 10 has been shown to be a clinically important difference in pain intensity [19], [20]. Hence, this was chosen as the primary endpoint for both the treatment (cordotomy) and control (comprehensive palliative care) arms of the study. Patients who were randomized to undergo cordotomy (Group 1) underwent assessment of their pain intensity on the day prior to the procedure. Patients randomized to continued comprehensive palliative care (Group 2) underwent assessment of their pain intensity on the day of enrollment into the study. Pain intensity was reassessed in person on postprocedure days 1 and 7 for Group 1, and 1 week after study enrollment for Group 2. The response rate for both the cordotomy and control groups was determined by the change in pain intensity between days 1 and 7.

Other metrics derived from the ESAS and the BPI were used as secondary outcomes. Specifically, the physical sum score, psychological sum score, and the global symptom distress were calculated from the ESAS. The patient's worst pain and pain interference score (mean of question 9 from the BPI) were also used as secondary metrics.

Patients in Groups 1 and 2 had careful documentation of their opioid and adjuvant medication requirements. The mean morphine equivalent daily dosage (MEDD) was calculated separately for Groups 1 and 2 on study days 1 and 8 [21], [22], [23].

Statistical Analysis

Descriptive statistics were used to describe baseline demographic and clinical data. For the primary outcome, the change in median pain intensity score was computed for each group using the Wilcoxon signed rank test. Median ESAS, BPI, and MEDD, as well as QST data, were also analyzed for each group separately using the Wilcoxon signed rank test. The adjusted p value (q value) was calculated using Holm's step‐down procedure for multiple testing.

Results

Over a 22‐month enrollment period between 2015 and 2017, palliative care clinic visits were screened by our study coordinator, and 35 patients were proposed for study inclusion to the palliative care physicians. From this group, 22 patients met the inclusion criteria for study enrollment and were refractory to optimal palliative care treatment. Of these 22 patients, 4 patients were in severe pain and did not want to risk being randomized to continued palliative care. These four patients received cordotomy separately from the study protocol. An additional two patients did not feel that their pain was severe enough to warrant interventional approaches for pain management (Fig. 1). Of the 16 patients enrolled in the study, nine were female and seven were male, with a median age of 58 years (range 38–76; Table 1). Seven patients were randomized to undergo cordotomy, and nine patients were randomized to continued comprehensive palliative care management. Recruitment was stopped at the end of the funding period.

Figure 1.

CONSORT flow diagram.

Table 1. Clinical and demographic data for 16 patients included in trial.

Primary Outcome

Six of seven patients (85.7%) randomized to cordotomy experienced a 33% reduction in pain intensity (PI). Among these seven patients, the median pain intensity reduced from a baseline PI of 7 (range 6–10) to a PI of 1 (range 0–6) 1 week after cordotomy (p = 0.022). In comparison, zero of nine patients (0%) randomized to palliative care achieved a 33% reduction in PI. The median pain intensity for the palliative care group changed from 6 (range 5–10) to 5 (range 4–10) 1 week after randomization (p = .097).

After 1 week, seven of the nine patients (77.8%) randomized to palliative care elected to undergo cordotomy. All of these patients experienced a 33% reduction in PI, with a median preprocedure PI of 8 (range 4–10) which reduced to a median PI of 0 (range 0–1) 1 week after cordotomy (p = .022; Table 2).

Table 2. Pain outcomes for cordotomy, comprehensive palliative care, and crossover groups.

^a p = .022.

^b p = .036.

Abbreviations: BPI, Brief Pain Inventory; ESAS, Edmonton Symptom Assessment Scale.

Secondary Outcomes

Patients who underwent cordotomy also experienced a significant improvement in metrics derived from the BPI (Fig. 2). The seven patients randomized to cordotomy had a reduction in their worst pain from a median of 9 (range 7–10) to a median of 3 (range 0–7) 1 week after cordotomy (p = .022; q = .31). Those randomized to medical management had no change in the median worst pain, which was 8 (range 5–10) preoperatively and 8 (range 4–10) 1 week after continued palliative care.

Figure 2.

Pain outcomes as reported by the patient with the Brief Pain Inventory. A significant reduction in “worst pain” was seen in patients randomized to cordotomy (n = 7) (A), whereas patients randomized to continued palliative care (n = 9) experienced only minimal further improvement in pain (B).

Of the 14 patients who underwent cordotomy, the median BPI worst pain was 9 (range 4–10), and the pain interference score was 7.6 (range 5.7–10) at baseline. At 1‐month follow‐up, 12 patients were alive for follow‐up with a median worst pain score of 0 (range 0–5) and a median pain interference score of 0 (range 0–5.7). Ten patients (83.3%) had worst pain score of 0 at 1‐month follow‐up. At the 3‐month follow‐up, five patients were alive for follow‐up, and two patients experienced a recurrence of their pain. Four patients were alive for follow‐up at 6 months postprocedure, and three of these four patients continued to experience significant improvement on the pain interference score, whereas two of four patients experienced worst pain scores >4 (Fig. 3).

Figure 3.

Long‐term outcomes for all patients who underwent cordotomy (n = 14) as determined by the worst pain score of the BPI (A) and the pain interference score of the BPI (B).

Abbreviation: BPI, Brief Pain Inventory.

With regard to opioid requirements, the median baseline MEDD for those randomized to cordotomy was 234 (range 30–507). The median MEDD at 1 week for this group was 90 (range 30–420, p = .027, q = .054). For patients randomized to comprehensive palliative, the median MEDD was 210 (range 96–765), which remained at 210 (range 120–765) at 1 week (p = .056, q = .056). The seven patients who underwent delayed cordotomy had a significant reduction of the MEDD from a median of 150 (range 120–1,520) to 30 (range 0–1,095) 1 week after the procedure (p = .016, q = .048).

Quantitative Sensory Testing

Among all 14 patients who underwent cordotomy, a significant increase in the threshold for pinprick sensation in the area of maximum pain was detected on the first postoperative day (median preoperative threshold 19.6 g, range 8–128 g; postoperative threshold 64 g, range 18.7–128 g; p = .0027, q = .030). Patients also experienced a significant increase in their sharpness detection threshold in their foot on postoperative day 1 (median preoperative threshold 34 g, range 12.6–128 g; postoperative threshold 96 g, range 16–128 g; p = .003, q = .030). No significant difference was seen in the hand sharpness detection threshold on postoperative day 1 (median 42 g, range 16–128 g; p = .46, q > .99). By day 7 after cordotomy, although there was an elevation in median sharpness detection threshold in the area of maximum pain (128 g, p = .02, q = .17), foot (77 g, p = .02, q = .17), and hand (64 g, p = .48, q > .99), these changes were not statistically significant.

A significant elevation in heat pain perception was observed in the area of maximum pain on postoperative day 1 (median preoperative threshold 44.3°C, range 37.2°C–49.7°C; postoperative threshold 47.8°C, range 40.3°C–52°C; p = .0002, q = .0024). No significant difference in median heat paint threshold was noted in the foot (47.9°C, p = .3, q = .2) or hand (46.8°C, p = .01, q = .12) on postoperative day 1. By postoperative day 7, there was a persistent elevation in median heat perception in all areas; however, these results were not statistically significant (area of maximum pain, 47.3°C, p = .04, q = .2; foot, 47.9°C, p = .48, q > .99; and hand, 47°C, p = .18, q = .72).

Complications

There were three complications observed among the patients who underwent cordotomy. One patient with preexisting prostate hypertrophy experienced urinary retention after the procedure requiring a Foley catheter. The Foley catheter was removed approximately 2 weeks later. A second patient had subjective weakness of the leg on the same side the cordotomy was performed. This patient had 4/5 strength in this limb, which improved to full strength over 2 weeks. The final patient experienced dysesthetic sensations on the previously painful side of the body. These sensations lasted for 1 week following the procedure.

Among the group randomized to continued palliative care, one patient had pain of such severity that she was admitted to the hospital for inpatient management prior to crossing over to cordotomy.

Discussion

The role of interventional approaches for the treatment of refractory cancer pain is not established. Early reports of neurosurgical approaches for pain management were limited by retrospective analyses, poorly defined outcome metrics, and uncertainty as to whether adequate nonoperative strategies had been used [9].

In this preliminary report, we have sought to address the limitations of previous reports. Notably, all patients who underwent cordotomy in this study were evaluated and treated by an interdisciplinary palliative care team on at least three separate occasions to optimize pharmacological and nonpharmacological strategies. As evidenced by a median baseline MEDD of 222 mg across all patients recruited to the study, aggressive opioid management was used for all patients in addition to other noninterventional strategies. In this subset of patients with medically refractory pain, we found that the majority of patients randomized to cordotomy had clinically meaningful improvement in pain, whereas patients randomized to continued palliative care did not improve further. It was also reassuring to see a significant decrease in the MEDD in patients randomized to cordotomy initially, as well as in those patients who crossed over to cordotomy after an additional week of palliative care.

The goal of cordotomy is interruption of pain modalities carried by the spinothalamic tract. In this study we assessed for changes in fast pain, as assessed by sharpness detection, and slow pain, as assessed by slow heat pain transmission. A significant increase in both these modalities was seen in the area of maximum pain on postoperative day 1. Although a significant change in pain thresholds was not observed on postprocedure day 7 when using a corrected p value, we hypothesize that persistent pain relief is associated with persistent elevations in fast and slow pain transmission.

Complications associated with cordotomy were generally mild. An observed transient neurological complication rate of 2/14 (14.3%) and an overall treatment complication rate of 21.4% were observed. No patient experienced permanent deficits.

This study has several limitations. Our estimate that we could recruit 30 patients per year to this study was inaccurate. We were able to recruit approximately eight patients per year to this study from a single department at a cancer institution. In addition, this study was performed at single center with a single surgeon and well‐established palliative care team, which may limit the generalizability of these results. Because the study was not blinded, there was also a potential for bias in patient reported outcomes that were used in this study. However, the reduction in median MEDD at 1 week in the cordotomy group supports the improved pain outcome scores recorded.

Despite limited patient recruitment during the study, the results of this study emphasize the advantages of an intervention like cordotomy, such as an immediate benefit conferred to the patient and the ability to perform the intervention even in advanced stages of disease (Fig. 4). Cordotomy is also a single intervention with no further surgical follow‐up needed. Cordotomy can be repeated if pain recurs, and one patient in our cohort underwent a repeat cordotomy 1 year after her initial procedure because of pain recurrence.

Figure 4.

Case illustration. (A): Ideal candidate for cordotomy to palliate pain. Unilateral nociceptive pain that is below the shoulder level. (B): Intraprocedural computed tomography scan demonstrating radiofrequency electrode within the anterolateral spinal cord, the location of the spinothalamic tract. (C): Postoperative magnetic resonance imaging performed on postprocedure day 1 revealing a lesion in the anterolateral quadrant of the spinal cord.

Conclusion

This pilot study provides supporting evidence for the use of cordotomy in medically refractory cancer pain. Using the response rates observed in this study, an adequately powered trial can be conducted to determine whether interdisciplinary palliative plus cordotomy is superior to interdisciplinary palliative care alone in reducing pain, improving quality of life and achieving patient goals for symptom management.

Author Contributions

Conception/design: Ashwin Viswanathan, Eduardo Bruera

Provision of study materials or patients: Ashwin Viswanathan, Jewel Ochoa, Akhila S. Reddy, Dhanalakshmi Koyyalagunta, Suresh Reddy, Eduardo Bruera

Collection and/or assembly of data: Ashwin Viswanathan, Aditya Vedantam, Kenneth R. Hess, Jewel Ochoa, Patrick M. Dougherty, Akhila S. Reddy, Dhanalakshmi Koyyalagunta, Suresh Reddy

Data analysis and interpretation: Ashwin Viswanathan, Aditya Vedantam, Kenneth R. Hess, Patrick M. Dougherty, Akhila S. Reddy, Dhanalakshmi Koyyalagunta, Suresh Reddy, Eduardo Bruera

Manuscript writing: Ashwin Viswanathan, Aditya Vedantam

Final approval of manuscript: Ashwin Viswanathan, Aditya Vedantam, Eduardo Bruera

Disclosures

The authors indicated no financial relationships.