1Pain Therapy, Humanitas Oncology Center, Catania Italy
2Radiotherapy, Humanitas Oncology Center, Catania Italy
3Radiology,Humanitas Oncology Center, Catania Italy
Summary A high percentage of patients with neoplasm develop osteolytic metastases that, in addition to causing pain, expose them to the risk of fractures and nerve compressions. Standard therapies with chemotherapy, radiotherapy and bisphosphonates are not always effective in controlling pain and the surgical treatment is reserved to patients in fair general conditions and with a long-life expectancy because of its high morbidity and mortality. Opioid medications may also not be well tolerated due to the side effects they cause. Recently, minimally invasive techniques have been introduced to control pain by acting quickly and with few complications. One of the most used is radiofrequency thermoablation (RFA) which, through the introduction of a thermal probe into the bone, causes metastasis necrosis and allows pain control.
Riassunto Un’elevata percentuale di pazienti con neoplasia sviluppa metastasi osteolitiche che, oltre a provocare dolore, espongono al rischio di fratture e compressioni nervose. Le terapie standard con chemioterapia, radioterapia e bifosfonati non sempre sono efficaci nel controllare il dolore e il trattamento chirurgico è riservato, a causa della sua elevata morbiditá e mortalità, a pazienti in discrete condizioni generali e lunga aspettativa di vita. Anche i farmaci oppioidi possono non essere ben tollerati a causa degli effetti collaterali. Recentemente sono state introdotte tecniche mini invasive per controllare il dolore che agiscono rapidamente e con poche complicanze. Una delle più impiegate è la termoablazione con radiofrequenza che, attraverso l’introduzione di una sonda termica all’interno dell’osso, provoca la necrosi della metastasi e il controllo del dolore.
Key words Osteolytic metastases, pain control, drugs, thermoablation, radiofrequency
Parole chiave Metastasi osteolitiche, controllo del dolore, farmaci, termoablazione, radiofrequenza
Up to 70 percent of patients with an established neoplasm develop osteolytic metastases1 and half of these will develop intractable pain, usually very severe, which could reduce patients’ quality of life by limiting mobility.2In addition to pain, osteolysis can also lead to fractures and nerves or marrow compressions (skeletal-related events, SRE).3 Since metastases spread more easily in bones with a greater proportion of hematopoietic bone marrow, the most frequently affected sites are vertebrae, pelvis, femurs, skull and,in a smaller measure, the other long bones.1 The neoplasms in the adult patients that most frequently lead to bone metastases are those of the breast, lung, prostate and kidney.4,5
Standard therapies include chemotherapy, bisphosphonates, radiotherapy and the administration of analgesics, often opioids.6 Metastases surgical treatments including vertebrectomy, reconstruction with cages, application of prostheses and other types of demolitive surgery, are often associated with long convalescence periods and with a high percentage of morbidity and mortality. For these reasons the surgical treatments are performed in patients with a long-life expectancy.6,7 In patients with advanced neoplastic disease, bone metastases may be less sensitive to chemotherapy and any additional radiotherapy treatment may not be possible due to adverse events (e.g. radiation induced myelopathy).6 Additionally, opioid drugs administered in rich doses can cause side effects that reduce quality of life.8 To overcome these limitations, minimally invasive techniques have been introduced in order to control pain andto limit SREswhere these have not already occurred.9-12As these are often patients with a significant burden of neoplastic disease, modest general conditions and limited life expectancy, treatments should act quickly and limit complications and side effects.13 Their purpose is almost always palliative even if under certain circumstances it can also be healing.3
Percutaneous radiofrequency thermoablation (RFA), introduced by Rosenthal in the mid-1990s for the osteoid osteoma treatment in the skeletal muscle system,14,15 is a percutaneous technique based on the introduction into metastatic bone, under CT or fluoroscopic guide, of a cannula that releases high frequency current (radiofrequency, RF), produced by a generator to which it is connected. The current released by the cannula induces in the surrounding tissue, through the Joule effect, a heating that when it exceeds 60 degrees causes an irreversible necrosis of the surrounding tissues. When used in place of the residual metastatic lesion it leaves a spheroidal zone of necrosis.3,16 The mechanism of action by which RFA causes pain relief is twofold and consists in the destruction by heating of periosteal nociceptors and in the reduction of interleukins and tissue necrosis factor (TNF), both responsible for sensitization of the A Delta and C nerve fibers as well as in the inhibition of osteoclasts.6,17
This case study reports on a 60 year-old caucasian male with a history of smoking for 35 years. In December 2017 he reported the appearance of algic symptoms in the left shoulder. Due to pain persistence, a shoulder radiography was performed, and it showed the presence of heteroplastic tissue. A thoracic CT was then performed with contrast agent which confirmed the presence of an oval-shaped swelling with polylobed and badly definable margins, located in the left sub-scapular muscle complex.
After a few days, he underwent a needle biopsy sampling of the neoformation. Due to the persistence of poorly controlled algic symptoms, the patient was admitted to our Pain Therapy Spoke Center where symptomatic analgesic therapy was prescribed consisting of etoricoxib 60 mg/day and a pre-constituted combination of oxycodone, 10 mg, and paracetamol, 325 mg every 8 hours. His pain was assessed as 8 using a numeric 10-points scale (NRS) where 0 means no pain and 10cthe strongest pain ever felt.18
The biopsy result showed the presence of malignant tumor cells referable to an adenocarcinoma with pulmonary origin. The patient responded promptly to drug therapy and shoulder pain was reduced from 8 to 5 NRS.
After a week, oxycodone was reduced to 10 mg every 12 hours and etoricoxib was suspended. Pain control remained stable. In January 2018, a CT was performed showing isodense tissue, probably lymph node, to the left pulmonary hilum. Subsequently, a PET with 18-FDG was performed and it showed an accumulation of osteomidullary tracerat the level of the scapula extending to the surrounding soft tissues. It also reported a tracer accumulation at the left pulmonary hilum and sacrum. In February 2018 radiotherapy treatment was performed at the left shoulder blade and on the sacral region (3000 cGy). After histological typing of the shoulder injury, chemotherapy with carboplatin, pemetrexed and zoletronic acid was performed. Despite this, there is a flare-up of the left shoulder pain (NRS 10) especially when the patient was laying down. The dosage of oxycodone and paracetamol was then increased respectively to 80 mg and to 1300 mg per day, but the pain was reduced only by 2 points (8 NRS) and moreover uncontrollable side effects (asthenia and drowsiness)were reported, which significantly limited the patient’s quality of life. Considering the oligometastatic spread of the disease, the lack of response to chemo and to radiotherapy, the poor response to analgesic therapy with high doses of opioids and the appearance of dose dependent side effects, the patient was offered to undergo to a local metastasis treatment by thermoablation with antalgic purposes. After explaining the procedure and its benefits and possible risks to the patient and receiving a written consent, it was decided to perform the RFA guided by CT, instead of fluoroscopic assistance due to the total absence of bone around the lesion and the proximity to the pulmonary parenchyma. The device used for the procedure consists of a straight probe connected to a radiofrequency (RF) generator, coaxial bipolar and internally cooled by water19designed to improve the quality and width of the ablation zone.Before starting the procedure, a metastatic lesion mapping was achieved utilizing a CT scan performed a few days before. The mapping consists in the evaluation of the lesion size, which in this case has an oval-shaped appearance and a size of 32 x28 mm, and its location with respect to the surrounding anatomical structures (Figure 1 and Figure 2).
Following the mapping, the best access pathway was identified, and which of the available probes with associated active tip lengths, was better to use. It was decided to use the larger probe with an active tip of 20 mm which generates a thermal injury ellipse of 21 mm in width and 29 mm in length (Figure 3).
On April 27, 2018, almost 12 weeks after the end of the radiotherapy treatment , the RFA procedure was performed under local anesthesia (Figure 4) and with mild intravenous sedation (midazolam 2 mg). The chosen access pathway was the one under the spine of the scapula in order to allow the placement of the active tip in the center of the lesion (Figura 5 e Figura 6).In this case the ablation default time was 15 minutes and the temperature reached at the center of the tip was 90-95 °C.
At the end of the procedure no cement was injected because of the lack of bone tissue that could hold it and the proximity of the pulmonary parenchyma. However, before the thermoablation, a bioptic sampling of the lesion was carried out through the same osteo-introducer trocar that is used for the thermal probe passage.
Both in the immediate post-operative and in the next 24 hours no pain intensity reduction was reported from the preoperative NRS score of 8. Starting from 48 hours after the procedure there was a progressive reduction of pain and on the fifth day of the post-operative period the value of NRS was reported at 2 and the patient gradually reduces the analgesic drugs, until their complete suspension. After 10 days, pain was reported like a nuisance and assessed as an NRS of 2. No procedure related complications were reported. The bone biopsy result is "Bone localization of poorly differentiated carcinoma compatible with a pulmonary origin". After 5 months from the procedure, pain remained steadily under control (NRS 2) in the absence of analgesic drugs. A total body CT of reassessment was carried out and it showed “A clear reduction of the lithic component with osteoblastic reaction and remodeling of the bone structure and the calcium deposition (33x28 mm before, 9x17 mm now) (Figure 7)”.
The case examined has caused some technical difficulties due to its peculiarities that have conditioned our behavior. First of all, the metastatic lesion had caused a complete and extensive erosion of the scapula bone tissue which in that anatomical site is quite thin. Therefore, there were two pain sources: one pain component was due to the erosion and the consequent bone instability and the other was due to surrounding tissues infiltration. The other peculiarity was the proximity to the pulmonary parenchyma. Both characteristics have led us to use a bipolar probe and to avoid the use of cement after thermal ablation, which we usually use when we perform a thermal lesion in the bone tissue.20The bipolar probe allows in fact a deposition of energy more focused that reduces the risk of injury to adjacent structures. Furthermore, the use of a water-cooled probe increases the control on the temperature, avoiding carbonizations and thus increasing the size of the ablation zone of the neoplastic tissue. This should hopefully increase the likelihood of disease local control.21 The use of biological cement injection into the bone (osteoplasty, OP) after RFA is motivated by the fact that the thermoablation changes the tumor consistency by destroying the cohesion of its cells. In this way we obtain not only a reduction of the neoplastic tissue but also the creation of a "thermal cavity" that allows a more controlled deposition of the cement.6,21,22In addition, RFA produces thrombosis of the intra osseous venous plexus which should reduce the risk of cement and tumor cells leakage into the veins.6,23-25 In turn, the osteoplasty OP would reinforce the acute analgesic effect of RFA thanks to the exothermic reaction produced by the cement when it hardens and should be responsible for a long-term effect thanks to its stabilizing action on the fractured bone.6,26,27This would happen regardless of the percentage of cement used, at least at the level of the vertebral body.28 However, some authors state that the release of polymethylmethacrylate (PMMA) cement into the necrotic cavity after RFA does not have a significant additional effect on pain reduction, supporting thus a direct relationship between tumor RFA and pain relief due to the nociceptors destruction and the reduced production of cytokines.13,29In fact, the guidelines of the National Comprehensive Cancer Network (NCCN) - version 2.2014 - list the RFA as a possible treatment for the bone pain local control.30 Ultimately, a synergistic effect between RFA and OP in pain control is still not demonstrated.31,32However, in this case report the injection of PMMA, in addition to not having any chance of stabilizing the bone due to the type of neoplastic erosion, would have exposed the patient to the additional risk of spreading the cement towards the nearby pulmonary parenchyma.
Our clinical case offers two relevant and encouraging key points. The first is to have obtained a very satisfactory antalgic effect where the previous radiotherapy, ended 12 weeks bef ore the RFA, had not achieved any improvement. This result is supported by previous observations on the improvement of the pain relief due to RFA when this technique is preceded by a radiotherapy treatment ineffective or impossible to administer due to the limit dose reaching.33The second key point is the ready and lasting analgesic effect obtained even if the osteolytic lesion was wider than the ablation zone performed by the thermal probe and therefore had not been able to ablate the entire surface between bone and tumor. In this regard, the literature data are conflicting and while some authors have observed our own phenomenon,13others state that if the thermal lesion does not involve the entire surface between tumor and bone the result will not be satisfactory.17
Finally, the unexpected reparative/reconstructive effect led by RFA on bone tissue, is worthy of mention. Due to procedures timing it’s indeed unlikely that it is due to radiotherapy effect. RFA has been performed almost 12 weeks after the conclusion of radiotherapy treatment and this is considered a timeframe bigger than the one for which you can observe radiotherapy effects.34To our knowledge, it has never been described before the RFA reconstructive bone effect. This effect could be attribute to the known osteclasts inhibition mechanism prompted by thermoablation. Probably, the frequent combination of RFA and OP has intuitively associated the stabilization and reconstructive merit to OP.
However, considering the characteristics of the osteolytic lesion, the reduction of the NRS value from 8 to 2 without taking any analgesic drug and the lesion reparation which dimensions decreased to one sixth of the initial ones in three months can be considered as a very satisfactory result even if the observation period after RFA is not particularly long. It is challenging to talk about adequacy in pain control in patients with a long-life expectancy.
Bone RF ablation of metastatic lesions is a widely known therapeutic option for pain control. Due to its minimal invasiveness it is usually performed when non-surgical treatment (radiotherapy, chemotherapy, bisphosphonates, opioids, etc) did not obtain satisfactory pain control. Our experience, even if restricted to a single case, show the potential bone reparative/reconstructive effect, that if confirmed in future studies in a broader population, allow a more widespread of the technique even without subsequent cement application.
Conflict of interests
The authors certify the study was conducted without conflicts of interests.