Interventional pain management

Due to the wide range of structures and multi-modal pathophysiology of pain in MPM, the resultant pain syndrome may be resistant to conventional pharmacological regimens, such as costopleural syndrome. In this syndrome, pain will often present with mixed nociceptive and neuropathic pain features as the autonomic, intercostal, and occasionally brachial plexus nervous structures are involved.32 In this instance, interventional techniques may be employed. It has been suggested previously that these techniques are used as an adjuvant to common analgesic regimens at any stage rather than seen as a last resort.33 In terms of MPM, the National Mesothelioma Framework has advocated that cervical cordotomy is an option to help alleviate challenging pain syndromes.34However, this treatment is not universally available, and there is variability in its provision in different areas.35

High cervical cordotomy involves the creation of a permanent lesion in the ascending pain pathways of the spinothalamic tract (often with heat created by radiofrequency) in the antero-lateral spinal cord. This is effective for unilateral cancer related pain below the level of the C4 dermatome, ie, below the shoulder.36 Cordotomy previously was performed as an open surgical procedure under general anesthetic with a wake-up test intra-operatively, but since the 1960s an awake percutaneous approach (percutaneous cervical cordotomy [PCC]) is most commonly employed.37


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The spinothalamic tract carries pain and temperature sensation to the brain from the contralateral side of the body, thus is useful in unilateral thoracic pain syndromes often found with MPM. The tract is approached most easily at C1/2 and thermoablation at this level controls pain below C4 on the contralateral side. The extent of analgesia depends on the position of the electrode within the tract (the fibers are arranged somatotopically) and also the size of the lesion created. Because PCC is selective for pain and temperature sensation, it achieves pain relief without numbness and preserves motor power and proprioception.37

A systematic review examining the use of cordotomy for mesothelioma-related pain in 2013, found that of nine included case series involving 160 patients, all studies showed good pain relief in the majority, the greatest benefits in pain reduction were seen in the initial-post procedure phase.35 Side effects, such as headache, motor weakness, and mirror pain, occurred relatively frequently but were transient in nature and respiratory dysfunction was rare. Overall, the quality and quantity of evidence was limited and the authors concluded that further data were needed to aid decision-making on its continued provision. This review advised that a registry be set up, and in 2014 a UK National PCC registry was launched with the Invasive Neurodestructive Procedures in Cancer Pain Registry. This registry has recorded over 200 cases prospectively, including the safety and efficacy of this technique.36 Data from this registry are awaited. A prospective study of 45 patients has shown that 80% of patients reported >75% pain relief from cordotomy at 4-week follow-up.36

The most recent European Society for Medical Oncology (ESMO) guidelines on the Management of Cancer pain in adult patients states that: “Cordotomy should be offered in a MDT setting with palliative medicine, oncology and pain medicine teams to support the care pathway.36 In the case of patients who are unable to tolerate percutaneous cervical cordotomy because of the intractable nature of pain and the incapacity to lie supine in theatre, surgical cordotomy remains an option”. They recommend that “Cordotomy should be available to patients with otherwise poorly controlled cancer-related pain”.

Other interventional techniques include peripheral nerve injections. A “nerve block” describes a procedure utilizing a needle to deliver a local anesthetic or an ablative agent, such as phenol, alcohol, or glycerine, for analgesic purposes.38 Diagnostic blocks may be employed initially to ascertain the correct anatomical area or afferent pathway to subsequently target with a permanent block. Patients with thoracic chest wall pain may benefit from procedures targeting the intercostal nerve, the posterior root of the thoracic radicular nerve, and the paravertebral space. Intercostal blocks and neurolysis can be done at the patient’s bedside. Due to the potential risk of pneumothorax, it is suggested that direct needle placement is guided by ultrasonography. The benefit is seen due to the loss of sensation distal to the point of injection following the path of the nerve toward the anterior chest wall.38 One series reporting intercostal procedures for chest pain management in patients with metastatic rib lesions showed that 56% of patients described reduced analgesic use post procedure.39When an intercostal nerve block provides temporary relief, the subsequent options are to repeat the block with a more permanent form of chemical neurolysis with agents, such as phenol,40 heat via radiofrequency,41 or freezing (cryoneuolysis).42

SURGERY

Surgery as part of a tri-modality approach is the most aggressive treatment option in MPM. Its role in survival outcomes and palliation of symptoms remains under debate with several approaches described. The most radical surgery is extrapleural pneumonectomy (EPP), which consists of en-bloc resection of the visceral and parietal pleura with the lung, pericardium, and diaphragm. This surgical approach is limited to select patients, as many are unfit for such radical management due to advanced disease, frailty, and multiple comorbidities.43 A systematic review by Cao et al44 reported a significant mortality rate following EPP of 0%–11.8% and morbidity of 22%–82%, resulting in a median overall survival of 9.4–27.5 months. Debate regarding EPP has continued following the Mesothelioma and Radical Surgery (MARS) feasibility study, which randomized patients to receive chemotherapy and best supportive care only vs induction chemotherapy, EPP, and adjuvant hemi-thoracic radiotherapy. The trial concluded that, although limited, the data suggested that EPP within tri-modality therapy offered no benefit and possibly harmed patients.45 This outcome received criticism for forming such a conclusion. The MARS researchers designed a feasibility trial due to the anticipated challenge in recruiting patients comparing EPP with non-surgical management. The objective was to assess the possibility of completing a larger trial to clarify the role of EPP and not designed with the outcome to test the benefit or absence of EPP. The power of the study was low due to the small number; 50 patients who were recruited over 3 years. Investigators of the MARS trial state that 670 patients would need to be identified to gain any significant difference on overall survivial between EPP and no EPP. Thus, due to the design and power of the MARS trail, it did not allow the outcome of surgery vs no surgery to be adequately assessed.46

In recent years, interest in the less aggressive surgical approach of pleurectomy and decortication (P/D) has grown. P/D involves the resection of both parietal and visceral pleura, sparing the lung parenchyma. Advancement in techniques has led to variants of P/D procedures which are utilized in both curative and palliative management. Extended P/D, which consists of parietal and visceral pleurectomy, removal of gross tumor with resection of diaphragm, and/or pericardium, is performed in patients with potentially curative intent as an alternative to EPP.47 Flores et al48 determined that patients who underwent P/D in fact had a decrease postoperative morbidity and mortality when compared to EPP. The review, however, importantly recognized the impact of selection bias outcomes on falsely inflating survival results. Concern, therefore, remains on the interpretation of whether EPP or extended pleurectomy and decortication provides more successful results. The MARS249 trial aims to resolve this issue and investigate the survival and patient reported outcomes with extended P/D following chemotherapy vs chemotherapy only.

Palliative debulking surgery and parietal pleurectomy are performed to provide symptom control in MPM. This type of surgery is not undertaken with a curative intent but removal of the visceral pleura, and relieve of a trapped lung can, reduce chest wall pain.50 Video-Assisted Thoracic Surgery (VATS) offers a minimally invasive alternative for patients who are unfit for radical EPP or extended P/D. Recurrent pleural effusion can cause dyspnoea and discomfort for patients with MPM. The MesoVATS randomized controlled trial51 compared video-assisted thoracoscopic partial pleurectomy vs talc pleurodesis for the management of pleural effusion in MPM. While VATS has the benefit of being a less invasive approach, it demonstrated no improvement in overall survival and this approach resulted in more complications and longer hospital stay. Results assessing patients quality of life demonstrated worse function at 1 month improving at 3, 6, and 12 months with VATS compared to tacl pleurodesis; but no significant difference between the groups was identified. As discussed previously, interventions for investigation or treatment can increase the risk of seeding of malignant cells along instrument tracts.23 While most surgical research does not focus on pain management, it clearly has an impact on morbidity and quality of life of patients. The complexity of radical surgery, and on-going debate as to its role, has led to the advisement of its use only within a multi-disciplinary framework, as part of a clinical trial at specialized centers.46

SYSTEMIC ANTICANCER THERAPY (SACT)

Chemotherapy is the first- and second-line treatment for unresectable tumors.52 While research has focused on chemotherapy’s role on patient survival, limited data focus on its effect on pain control. At present, the most widely used regimen for patients with unresectable MPM consists of cisplatin with pemetrexed. This standard treatment resulted following the publication of the Phase III EMPHACIS trial,53 a large-scale randomized controlled trial which involved 456 chemotherapy-naive patients to receive cisplatin and pemetrexed or cisplatin alone. Patients treated with the combination of pemetrexed and cisplatin had a greater survival time of 12.1 months compared to 9.3 months, as well as superior response rates and progression-free survival when compared to patients who received cisplatin alone. The addition of vitamin supplementation also demonstrated a reduction in toxicity. A modified version of the Lung Cancer Symptom Scale underwent formal validation in patients with MPM and was administered to patients of the EMPHACIS trial. Results from the 90% of patients who completed the questionnaire which was presented by Gralla et al54 at ASCO 2003 reported an improvement of overall symptom score in patients receiving combination chemotherapy, with a statistically significant improvement in pain, cough, and dyspnoea by cycle 4, week 12 in patients receiving pemetrexed plus cisplatin. The addition of bevacizumab, an anti-vascular endothelial growth factor, to current standard chemotherapy, of pemetrexed and cisplatin, has been highlighted following the MAPS study.55 This multi-center Phase III trial of 448 newly diagnosed patients with MPM randomly allocated patients to standard treatment or in combination with bevacizumab,. The addition of bevacizumab to standard chemotherapy resulted in an increase in median survival to 18.8 months in the bevacizumab arm compared to 16.1 months with standard chemotherapy. Westeel et al56presented the MAPS trial results of its treatments impact on patients quality of life at ASCO 2018. The results of health-related quality of life were assessed in 95.5% of patients through use of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire QLQ-C30 and the Lung Cancer specific module QLQ-LC13. The addition of bevacizumab to cisplatin and pemtrexed significantly improved patients pain (HR 0.81, 95% CI 0.67–0.99; P=0.041) and peripheral neuropathy (HR 0.73, 95% CI 0.6–0.89, P=0.002). These results demonstrate that chemotherapy plays a role not only in overall survival but also provides symptomatic relief in MPM. Unfortunately, most MPM patients progress following first-line chemotherapy. No optimum regimen has yet been identified for second-line treatment.57

Careful balance between symptomatic improvement, at the risk of chemotherapy toxicities, remains a challenge as MPM patients progress. For fragile or elderly patients, carboplatin is often substituted for cisplatin. This aims to decrease toxicity, and in fact, has been reported to have similar outcomes between patients treated with cisplatin and pemetrexed.58 A focus on active symptom control in MPM patients was highlighted by the randomized control trial by Muers et al.59 This trial was undertaken before the identification that the addition of pemetrexed was demonstrated to provide superior survival outcomes. The trial reviewed the impact of first-line chemotherapy on survival compared to active symptom control alone. Four hundred nine patients were randomly assigned to receive symptomatic treatment alone, symptomatic treatment and chemotherapy, including cisplatin, vinblastine, and mitomycin, or symptomatic treatment plus single agent vinorelbine. Unfortunately, the numbers were insufficient to determine a benefit between chemotherapy regimes, although a trend toward a survival benefit for patients receiving single agent vinorelbine was noted. Ultimately they concluded that addition of chemotherapy to symptom control offered no significant benefit in terms of overall survival and quality of life. Given the current recognition of superior survival outcomes with the addition of pemetrexed, updated research would be welcome to review the impact of current first-line chemotherapy on survival compared to active symptom control alone.

As with many other tumor sites, interest in immunotherapy treatment is growing, particularly in a disease like MPM where treatment options are limited. Immunotherapy aims to stimulate the body’s natural ability to fight cancer. At present, immunotherapy is not a standard treatment for MPM.52Agents including check point inhibitors are being investigated as potential treatments for MPM. Pembrolizumab, a programmed death-1 (PD1) inhibitor, is currently under review for its impact on MPM. The PD1 receptor is a checkpoint which when triggered by either of its ligands (PDL1 or PDL2) initiates apoptosis of effector T cells and preservation of regulatory T Cells. One percent of cells express PDL1 in up to 40% of MPM tumors. Checkpoint inhibitors interrupt the cancers ability to co-opt this pathway and silence the immune systems antitumor response.60 A Phase 1b trial of 25 patients with PDL1 expressed in 1% of tumor cells demonstrated a response to treatment with Pembrolizumab. Disease control was seen in 18 patients, who had a response duration of 12 months. Immune-related adverse effects were observed in three patients with grade 3 treatment-related toxicity observed in another five.61 This promising response has led to the PROMISE–meso Phase III randomized control trial comparing prembrolizumab with gemcitabine/vinorelbine in MPM.62 Research into combination of PD1/PDL1 agents in combination with CTLA-4 agents have been assessed for second or third-line treatments options in the MAPS2 trial.63 This randomized 125 patients to receive single-agent nivolumab or combination nivolumab and ipilimumab (a CTLA-4 agent). The results were favorable to other second or third-line therapies, which on average have a 3-month progression-free survival. Nivolumab monotherapy had a medial progression-free survival of 4 months while combination therapy was 5.6 months. Serious adverse events, however, including three patient deaths from treatment-related complications following combination therapy, was highlighted. Outcomes of such trials will advance knowledge to the promising potential immunotherapy presents in the management of MPM.

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