DISCUSSION
Primary pediatric spinal tumors are rare, however, up to 5% of children with extra-spinal solid malignancies develop metastasis to the spine secondary to contiguous invasion or hematogenous spread8. When curative intent is no longer achievable in patients with spinal malignancies, the main goals of treatment shift towards preservation of function and improving quality of life via pain control. Cancer-related pain can pose significant psychological and physical burden to pediatric patients, resulting in a negative impact on quality of life 9. Adequate palliative pain management can be challenging, requiring multimodality treatment strategies to provide adequate control. This may include oral or intravenous medications, surgery, radiotherapy (RT) and minimally invasive procedures such as thermal ablation or cementoplasty10.
Prescribing opioids is a valid initial strategy and is recommended by the World Health Organisation in their two-step approach for the treatment of severe cancer-related pain in children10,11. However, opioids have a well-established side effect profile including constipation, drowsiness, pruritis and nausea12. In addition, opioids pose other risks, such as tolerance, withdrawal, and dependence syndrome. For patients with pain refractory to optimized opioid dose escalation and despite other adjuvant medications (e.g., gabapentin or amitriptyline), alternatives become limited.
Continuous intravenous infusions of lidocaine or ketamine have been used to treat pain that is refractory to opioids 13,14. Lidocaine infusion, unfortunately, requires admission to the intensive care unit for continuous monitoring during drug initiation and dose titration due to risks of bradycardia, respiratory depression and seizure 13. Courade et al . recently published a prospective multicentric trial to evaluate the efficacy of continuous infusion of low-dose ketamine through the course of three days as adjunctive therapy in 38 children and adolescents with persistent pain14. Most of the patients in this study were being treated palliatively for solid malignancies and 97% of them were already receiving intravenous morphine for pain management. The continuous infusion of ketamine significantly reduced the visual analog scale of pain (VAS) in 50% of the studied population. However, opioid-sparing effect was only achieved in four of the 38 patients. More worrisome, 23% of the enrolled patients experienced poor tolerance to the trialed treatment. Even though these studies included patients with different tumor histologic types, they show that even non-invasive therapies may have complications and limitations. The potential advantages of vertebroplasty over infusion therapy might include shortened hospital stay after the procedure, elimination of the need for intensive care monitoring, the procedure being well tolerated even in young children, and the reduction in dose or elimination of the need for opioids following the intervention. Nevertheless, comparative prospective trials are needed to confirm these benefits.
Surgery for patients with advanced spinal tumors usually does not have a curative intent 15. The most common surgical techniques in this population include laminectomy for spinal cord decompression, resection of metastatic intraspinal tumors to prevent neurological compromise, or removal of epidural disease to allow radiotherapy. Surgery frequently requires posterior stabilization with instrumentation to prevent instability 16. Overall, invasive spine surgery in children poses a significant morbidity with reported complication rates at 19-21% and include spinal cord shock and nerve root damage, with an inpatient mortality rate of 3%16,17. In patients with refractory pain and with poor oncological prognosis, minimally invasive techniques may provide a more reasonable option, especially if life expectancy is thought to be short. In this study, recurrent pain was observed only after disease progression and few weeks before the patients passing.
RT has an important role in the palliative treatment of pediatric spinal tumors 18. A survey involving an international research consortium found that the most common indication for palliative radiation was pain management (43%), with the spine being the second most common targeted area (14%) 19. Rao et al.20 described pain relief in 83% of their treated patients, with 43% able to decrease their daily dose of opioids20. When compared to curative RT, palliative RT is better tolerated and has fewer side effects, with a grade ≥3 toxicity occurring in only 4% of patients 20,21.
Nonetheless, palliative RT still represents a small percentage of the indications in children when compared to the adult population19. Part of this may be explained by the fact that fewer investigations have been published in the pediatric literature and most practices are translated from the adults guidelines22. Another potential factor limiting the use of palliative RT in children may be the logistics involved in treatment. Younger patients may require anesthesia for adequate immobilization, and parents may face economic challenges involving travel costs and time away from work 19,23. These can be problematic since palliative RT regimens frequently require multiple sessions21. It is also important to note that, as the median survival after palliative RT is 3.6 months, a patient having to repeatedly come to hospital for RT may not be ideal20. Vertebroplasty has the advantage of being able to be performed in a single setting, thereby decreasing the number of hospital visits and potential costs involved. Future cost-analysis studies are necessary to confirm this hypothesis.
Percutaneous vertebroplasty is a minimally invasive image-guided procedure that injects PMMA cement within a collapsed vertebral body, to provide pain relief and mechanical stabilization. The cement polymerisation generates an exothermic reaction, destroying tumor and bone nerve endings within a 3 mm margin of the cement7. Additionally, the cement consolidates and stabilizes fractured fragments and prevents further vertebral body collapse 7. Vertebroplasty is recommended by several adult medical societies for the palliative treatment of painful oncologic fractures or weakened vertebral bodies secondary to neoplasms, with a reported clinical success of 92% and major complication rate < 1% 24–29. Vertebroplasty can be performed under conscious sedation or general anesthesia and takes approximately 15-30 minutes, with an increment of 5-15 minutes for any additional vertebral level treated 7.
Vertebroplasty is associated with significant pain reduction and increase in the level of function, with sustained long-term benefit. A recently published systematic review included 1445 adults with spinal malignancies that underwent palliative vertebroplasty alone for the treatment of painful pathologic fractures 30. Baseline weighted average Oswestry Disability Index (ODI) was 74.7, with a Visual Analog Scale (VAS) of 7.5. Both scores significantly decreased following intervention and demonstrated sustained long-term benefit, with ODI of 28.9 and VAS of 3.0 after 1-year follow-up 30. This publication also confirmed the safety profile of the procedure, with a very low incidence of symptomatic complications (1.4%), which included radiating pain, transient chest pain, radiculopathy without palsy, hemothorax, hematoma, radicular neuritis, asymptomatic and symptomatic pulmonary embolisms, bilateral leg motor deficits, cauda equina, and complete paraplegia. Pain might increase immediately after the procedure and is likely related to muscular spasm, and the full pain relief benefit following intervention may take up to two weeks. Cement leak can occur but the vast majority are asymptomatic and usually of no clinical significance 30. Since these studies were performed in adults, the true benefit and complication risks in the pediatric population still needs further investigation.
All three patients treated with vertebroplasty in this retrospective study described significant pain improvement, with Patient 1 and 2 no longer requiring oral medications. Few cases of vertebral augmentation for pain control have been reported in pediatric patients and are summarized in Table 2 31–35. Patients were treated with kyphoplasty and vertebroplasty in four of the five case reports and only two of the eight patients that were treated had an underlying malignancy 33,34. There is no evidence of clinical superiority of kyphoplasty over vertebroplasty, nor demonstration of lower incidence of complications 36. Kyphoplasty may require longer procedural times due to its increased technical complexity, has higher equipment costs, and typically requires larger needles for access which theoretically could increase complication risks36.
Vertebroplasty in the pediatric setting could potentially affect the normal development of the vertebral body due to mechanical restriction of growth or thermal disruption of the growth plate. Nonetheless, this has not been observed by other authors after a mean follow-up of 3 years (ranging from 3 months to 8 years) [34]. In pediatric patients with spine metastasis, the median survival of those who have the need to undergo radiation therapy or surgery, or who develop a pathologic fracture or spinal cord compression, is less than one year37. Therefore, the theoretical concerns of growth restriction should be weighed against the patient’s symptoms and potential benefit of the procedure.
Although the patients in the current study had pain secondary to metastatic disease to the spine, vertebroplasty could be useful in managing pain in other pediatric oncological scenarios. For instance, in patients with acute lymphoblastic leukemia (ALL) since up to 16% may have vertebral fractures at the time of diagnosis 38. Additionally, vertebroplasty could be a useful treatment in patients who develop painful vertebral fractures due to treatment-induced osteoporosis 39. Since these indications were not assessed on the current study, further investigation is required.
This study has several limitations. First, it is retrospective and did not allow for homogeneous assessment of patient reported outcomes or quality of life measures to capture the overall impact of the intervention. Second, the number of patients included is very small. In addition, all three patients had metastatic disease to the spine rather than a primary bone-based malignancy, and the application of this intervention in patients with primary spine tumors is still unknown. Patient 1 received neoadjuvant chemotherapy at the time of vertebroplasty, and Patients 2 and 3 had received recent palliative radiation prior to the procedure. This may confound the reported improved pain post vertebroplasty and make it challenging to truly quantify the overall impact of the intervention. However, in all three cases where vertebroplasty was performed, there was significant reduction in pain and medication use, and there was evidence of sustained tumor and pain response in two cases. This improvement would be consistent with published data in the adult literature.
In conclusion, vertebroplasty in children with spinal bony metastases may provide improved pain control with attendant reduction in the need for pain medications. This procedure could provide an additional option to accompany medical or radiation therapies for pain control in the palliative context and increased awareness of this treatment option could improve the quality of life for children and adolescents with vertebral tumors.
Conflict of Interest StatementThe authors have nothing to disclose.