As previously discussed, the excess morbidity and mortality conferred by EPP appears to be a limiting factor for trimodality therapy, with a large proportion (50-58%) of patients being unable to complete all treatment modalities largely due to surgical complications or progressive disease during treatment (81, 82). A retrospective review by DePerrot et al(81) found only half those who attempted trimodality therapy completed the full course of treatment. All patients received at least 3 cycles of induction cisplatin-based chemotherapy. One quarter (25%) did not proceed to surgery due to unresectability or progression of disease. Another 25% did not proceed to radiotherapy due to post-operative complications, poor functional status after surgery or further progressive disease. There was a perioperative mortality rate of 6.7%. The median OS was 14 months, with a 5-year survival rate of 10%. Multivariate analysis demonstrated that N2 disease was the most significant prognostic marker of worse outcome.
Treatment related complications and morbidity was also a major limiting factor identified in the EORTC Phase II trial (82) which aimed to administer trimodality therapy to 57 patients with resectable MPM. Less than half the studied population (42.1%) were able to complete the full course of treatment within prespecified timeframes. The median OS in this group was 18.4 months. Chemotherapy has been increasingly utilised in trials with or without cancer directed surgery for MPM(63) – likely due to the landmark trial in 2003 by Vogelzang et al(1), which demonstrated survival benefit with the use of combination platinum based treatment in unresectable MPM.
A systematic review (74) identified eight studies that utilised chemotherapy in the neoadjuvant setting and a further 8 that used adjuvant chemotherapy as part of trimodality treatment of MPM. The outcomes were difficult to compare given that the chemotherapy regimen, patient selection, follow up periods and reporting of survival outcomes varied between the trials. Overall, studies of adjuvant chemotherapy as part of trimodality therapy reported median OS periods of 19-24 months and median disease free survival of 10-15 months(74).
Trials involving neoadjuvant chemotherapy were similar in outcomes, with median OS 16.8-22.5 months and disease free survival of 10.1-16.3 months(74). Four of the more recent prospective phase II trials(82-85) using neoadjuvant chemotherapy, EPP and adjuvant radiotherapy showed that majority of patients (55-71%) completed trimodality treatment on an intention-to-treat analysis, and the perioperative mortality was 0-5%.
Complications from adjuvant radiotherapy is a limiting factor in delivering trimodality therapy. As the pleura has a large surface area, the volumes required for conventional radiotherapy is high. When radiotherapy is utilised after lung-sparing radical surgery (i.e. extended pleurectomy and decortication, rather than EPP), there is a risk of radiation-induced pneumonitis to the ipsilateral lung. Effective adjuvant radiotherapy aims to improve locoregional disease control with adequate delivery of radiation dose, while minimising excess radiation pneumonitis.
A phase II trial of adjuvant hemi-thoracic RT (54 Gy) following EPP demonstrated high rates of local control, with only two isolated loco-regional failures in 54 patients and a median survival of 17 months(86). The SAKK 17/04 trial (87) was a phase II randomised study that compared radical radiotherapy or no radiotherapy in patients who achieved complete macroscopic resection after induction platinum-based chemotherapy and EPP. Complete macroscopic resection was achieved in 64% of the study cohort, however only 35% of the cohort were randomised for radiotherapy, mainly due to patient decision not to participate. Most patients completed radiotherapy (median dose of 55.9 Gy) and there was one death from radiation pneumonitis. The authors found no survival benefit of additional hemithoracic radiotherapy despite better locoregional control. Overall, the authors concluded routine hemithoracic radiotherapy could not be recommended after induction chemotherapy and surgery.
Intensity modulated conformational techniques have been used to allow more effective sparing of adjacent structures and higher dosimetric control. A potential disadvantage of intensity modulated radiotherapy (IMRT) after EPP is the dose of radiation delivered to the contralateral lung and the risk of pneumonitis(88). Pulmonary toxicity is dependent on both lung volumes and the radiation dose. IMRT is also particularly useful after extended P/D as patients have both lungs in situ.
A single arm Phase II study of hemithoracic IMRT(89) after induction chemotherapy and (if feasible) extended P/D showed median progression-free survival of 12.4 months and OS of 23.7 months. The two-year OS was 59 percent in patients with resectable tumours and 25 percent in patients with unresectable tumours. A follow-up retrospective study (90) suggested that outcome was better with pleural IMRT, compared to conventional techniques.
While we await the results of the MARS2 study assessing multimodality therapy in the context of the extended pleurectomy and decortication, it is important to highlight that any such aggressive treatment approach should be limited only to high volume centres with appropriate surgical and post-operative expertise and resources, and as such should be considered inappropriate in the majority of developing nations.
Palliative Pleurectomy and Decortication
As most patients with MPM present with advanced, unresectable disease, most surgical procedures are undertaken with palliative intent to improve symptoms related to malignant effusions or tumour burden. Partial (debulking) pleurectomy with or without decortication is utilised for patients with MPM to improve symptom burden and improve QoL, particularly in those patients where visceral pleural disease limits lung expansion. A systematic review by Cao et al (2013)(66) showed that perioperative mortality ranged 0-7.1% for palliative P/D, with morbidity ranging 13-48% and marked heterogeneity in median OS (8.3-26 months) between studies. These findings are not dissimilar to those assessing partial pleurectomy with regard to mortality (0-7.8%), morbidity (14-20%) and OS (7.1-14 months).
To date, no clear survival benefit has been demonstrated for these procedures, however symptomatic benefits in dyspnoea and pain have been seen. A prospective cohort study (91) of 116 patients receiving partial pleurectomy (n=17) and decortication (n=34), reported a 30-day post-operative mortality rate of 7.8%, and significant morbidity (e.g. persistent air leak more than 7 days) was noted in 15% of the open decortication group. The type of procedure did not influence survival and symptom benefits in dyspnoea and pain were seen at 6 weeks and 3 months post procedure – however mortality from progressive disease outweighed the symptomatic benefits after this point. Multivariate analysis identified a select group of patients (epithelioid histology, no weight loss) who were more likely to retain symptomatic control with palliative surgery (p<0.01). We await the results of the MESO TRAP trial, which is an ongoing phase III study comparing VATS-partial pleurectomy/decortication vs. indwelling pleural catheter in patients with trapped lung due to MPM.
Pleuroedesis and Indwelling Pleural Catheters
Most (95%) patients with MPM develop pleural effusions which cause decrement in QoL without intervention. Pleurodesis is a palliative procedure where permanent pleural apposition is achieved through chemical or physical means – commonly through instillation of talc. Talc pleurodesis is a conventionally recommended intervention to control symptomatic effusions, mainly based on extrapolated data from studies in malignant pleural effusions with metastatic carcinomas. It is generally considered a safe procedure despite procedure related complications (mainly pain and fever resulting from intense pleural inflammation) and low reported rates of infective complications (3%) (92) or fatal acute respiratory distress syndrome (RDS) (93). Talc is an inexpensive substance that is available worldwide including in developing nations(94).
The optimal method of pleurodesis remains uncertain. Surgical pleurodesis is one method of creating pleural apposition through mechanical abrasion or parietal pleurectomy via thoracotomy or VATS has replaced open thoracotomy as the first line surgical procedure of choice in many developed nations(95), in developing nations with limited access to VATS, a traditional open surgical approach may be utilised – however with expected increased risk of morbidity.
An Australian registry based retrospective study of 390 patients between 2004-2009 found 165 (42.3%) patients had pleurodesis (surgical n=78; bedside talc n=86, bleomycin n=1)(92). Most surgical pleurodesis was performed during VATS and all involved talc poudrage. A completely successful pleurodesis (no further fluid accumulation) was achieved in 29.7% and partial success in 38.8%. No differences were seen in treatment success rates between surgical and bedside pleurodesis. Surgical pleurodesis was more often performed in younger patients (median age 67.1 vs. 72.3 years, p<0.01) and at time of diagnostic procedures, compared to bedside talc instillations.
Median survival was longer in those who underwent pleurodesis (443 vs. 193 days; p= 0.002), with better outcomes in those with completely successful pleurodesis. These findings are similar to prospective randomised trials assessing surgical and bedside pleurodesis for malignant effusions have found no advantage of VATS talc poudrage over bedside pleurodesis (93).
MESO-VATS(96) is the only RCT comparing VAT partial pleurectomy (VAT-PP) and talc pleurodesis in patents with MPM and pleural effusion. Both interventions provided similar, significant reduction in pleural effusion (70% VATS vs. 77% talc), without difference in overall QoL outcomes. Survival was similar in both arms at 12 months. Overall, the less invasive approach would beecommended to control pleural effusion, especially as a palliative procedure.
An alternative method of managing recurrent pleural effusions is an indwelling pleural catheter (IPC). IPCs are silicon tubes tunnelled and secured subcutaneously, ending in a one-way valve. It allows ambulatory drainage of pleural effusions to provide symptom relief without needing to create pleural apposition. IPCs can be more useful, particularly in those patients with visceral pleural involvement from MPM where pleural apposition may not be possible due to limited lung re-expansion. Other benefits include reduced length of stay (LOS) and lower rates of subsequent thoracocentesis (97).
A systematic review(98) of RCTs of talc pleurodesis in malignant pleural effusion found IPCs were associated with shorter procedure-related hospital stay and lower risks of further ipsilateral pleural interventions when compared with chemical pleurodesis. Conversely, IPCs were associated with a higher risk of cellulitis. There were no differences in control of dyspnoea or survival. The drainage regimen should be symptom-guided, with no difference between daily drainage vs. symptom guided drainage in providing symptom relief from dyspnoea in a randomised trial (AMPLE-2)(99).
There are multiple potential issues with IPC including additional cost and expertise required for tunnelled placement. Where IPCs are not accessible, repeated thoracocentesis would be a reasonable alternative. IPC s are also associated with infections – however reported rates of empyema and cellulitis are low (2.8% and 3.4% respectively)(100). Immunosuppression from chemotherapy did not increase pleural infection rates from IPC(101, 102). There is also risk of catheter related pain, symptomatic loculations, catheter blockage and fracture and protein depletion (103). Catheter tract metastasis is uncommon and recommended to be treated ad hoc with radiotherapy if accessible.
Recommendations for Surgical Interventions and Procedures in Developing Nations
Although the appropriate method of surgical management of mesothelioma remains controversial, trimodality therapy including EPP and eP/D should only be undertaken in specialist centres with expertise and resources, and ideally within a clinical trial setting. It is considered inappropriate for extensive operative management including EPP and eP/D to be considered outside of high volume, experienced centres with appropriate post-operative support including the availability of intensive care units. It is therefore not recommended this be undertaken in resource limited settings.
We recognise there is wide variability between and within developing nations in the availability of palliative surgical interventions for MPM such as partial pleurectomy and decortication, VATS pleurodesis or IPCs. The decision regarding appropriate modality is highly dependent upon the resources available and patient access to these. As such, pleural drainage (either intermittently through thoracocentesis, with or without the use of talc pleurodesis) remains the minimum standard of care globally including in low resource nations.
Palliative Care
Palliative care is the active management of patients with life-limiting, progressive, malignant, and non-malignant illnesses. This approach aims to improve the QoL of patients and their carers/families through prevention and relief of suffering, through assessment and treatment of physical symptoms as well as psychosocial and spiritual issues. For MPM, palliative care is applicable at any time between diagnosis and death and is provided concurrently with anti-cancer therapies with the aim of enhancing QoL, comfort and preserving dignity. The palliative management of symptoms are described further in Section 4: Patient Support.
Table 5: The World Health Organisation Definition of Palliative Care (104)
Effective palliative care is necessary in the management of patients with mesothelioma as an aggressive malignancy with high symptom burden, limited treatment options and short prognosis. In low resource settings, it is likely most palliative care will be delivered by community health care workers, rather than a specialist palliative care service. The 2018 Lancet Commission on Palliative Care and Pain Relief (105) describes significant inequity across the globe in relation to access to palliative care and opioids.
Globally, the need for palliative care is large and continues to grow. There are existing barriers to accessing opioids in low- and middle-income countries (LMIC), including lack of policy and investments into palliative care in addition to regulatory hurdles due to fear of non-medical use of opioids and side-effects. The Lancet Commission report also outlines an “essential package” of essential human resources, equipment and medications that form the basic inputs required for the safe and effective provision of essential palliative care in a primary care setting. The listed medications are also present on the WHO List of essential medicines and only includes off-patent formulations obtainable at low cost. The essential package also recommends that frugal innovation to provide for necessary equipment and empowerment, training and supervision of community health-care workers is an essential part of effective and safe delivery of palliative care and analgesia in low-resource settings.
Pain
Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or describe in terms of such damage(106). Pain in MPM can present with mixed nociceptive and neuropathic features owing from direct infiltration of soft tissue, bone and intercostal nerves(107). Pain for patients with MPM can therefore be complex and challenging, requiring a multi-faceted approach for effective management. In the Lancet Commission’s essential package for palliative care, five of the listed essential medications are commonly used in the management of cancer pain (morphine, amitriptyline, ibuprofen, dexamethasone, and paracetamol). The WHO’s 1986 Analgesic Ladder for Cancer Pain Relief (108) describes a 3-step approach to provide adequate pain relief for cancer patients, attempting to match the type of analgesia to the intensity of pain.
Additional recommendations supporting the implementation of the WHO analgesic ladder in cancer pain recommend that oral analgesia should be prescribed where possible to grant patients more control over pain management. Analgesia should be given with appropriate guidance and education and be given at regular intervals “by the clock” according to expected pharmacokinetics. If available, slow, or modified release formulations of opioids can be given regularly with short-acting formulations for ‘break-through’ pain. There are no standard doses for opioids for the treatment of cancer pain. Analgesia should be titrated and adapted to each individual patient and their pain intensity (See also Section: Patient Support). In the multi-center European Pharmacogenetic Opioid Study (EPOS) study(109), the mean total daily oral morphine equipotent dose for patients with mesothelioma ranged from 30.0 – 960.0mg (median 160mg). Half (50%) of the mesothelioma cohort were also taking systemic steroids. Only a minority (18%) of patients achieved complete control of pain. Where accessible, radiotherapy should additionally be considered for control of pain related to MPM. The SYSTEMS study (2015) demonstrated a clinically significant improvement in pain with radiotherapy (20Gy in 5 fractions) assessed at Week 5.
Furthermore, when other simpler measures have failed and where available, interventional procedures can also be considered for local control of pain. This may include peripheral (e.g., intercostal) nerve block or neurolysis. This involves injection of a local anaesthetic or ablative substance (e.g., alcohol) to induce loss of sensation in the distal neural distribution with analgesic intent. One series of intercostal blocks in patients with advanced cancer and painful rib metastases showed 56% described reduced analgesic requirements post-procedure (110).
High cervical cordotomy has also been described for palliation of pain in mesothelioma. This involves intentional damage to the ascending pathways of the spinothalamic tract in the antero-lateral spinal cord. This aims to reduce afferent, unilateral pain sensation below the level of C4. Although a systemic review(111) has shown effective, mostly short-term relief of pain when used in patients with MPM, the evidence base is small and carries potentially significant procedural risk (headache, mirror pain, motor weakness, respiratory dysfunction). This should only be undertaken in experienced tertiary centres.
Other palliative therapies, such as chemotherapy, see text on Systemic Therapies.
Dyspnoea/Cough
Dyspnoea and cough from MPM can be multifactorial, distressing, and difficult to control. Management is aimed at identifying the underlying causes, treating what is reversible, whilst also actively reducing the symptom burden with appropriate pharmacological and non-pharmacological interventions and strategies.
Appropriate examination and investigations should be undertaken to determine the underlying causes as dyspnoea and cough can be related to both malignant (e.g., pleural effusion, trapped lung) and non-malignant causes (e.g. infection, chronic obstructive pulmonary disease (COPD), heart failure, anaemia and anxiety). Recurrent malignant pleural effusion remains a major cause of dyspnoea in patients with MPM. Please refer to Chapter 3.4 for discussion of pleurodesis and indwelling pleural catheters.
A hand-held fan is a portable and cheap device which has been shown to alleviate chronic breathlessness(112). Although the mechanisms are not fully understood, airflow has been postulated to influence afferent sources for respiratory sensation. Several trials(113-115) have found significant reduction in severity of dyspnoea from short-term use of a hand-held fan in patients with chronic breathlessness. In addition, patient education about breathlessness in addition to anxiety reduction training (such as intentional diaphragmatic breathing and relaxation techniques) can be helpful in managing the fear/anxiety associated with dyspnoea.
Hypoxia is an end consequence of many conditions associated with MPM causing dyspnoea. Oxygen is listed as an essential device in the Lancet Commission’s Essential Package for Palliative Care and should be provided where accessible to alleviate dyspnoea. In those who are mildly hypoxic and without access to domiciliary oxygen, room air administered via nasal cannula at 2L/min can also be a potential alternative to palliate symptoms. A double-blind, randomised study of 239 participants with life-limiting illness, refractory dyspnoea and PaO2 > 7.3 were randomly assigned to receive oxygen or room air at 2L/min for 7 days. There was no additional benefit of oxygen in this setting(116).
Opioids have also been used in populations with life limiting disease and refractory dyspnoea with good effect. A systematic review and meta-analysis(117) showed a statistically significant, positive effect of opioids on the sensation of breathlessness (p=0.0008). Meta-regression of subgroups showed a greater effect for the oral or parenteral route compared to nebulised opioids. Opioids have also been used with good effect in patients with terminal lung cancer with refractory dyspnoea at rest(115).
Benzodiazepines are also frequently used as an adjunctive therapy to opioids in patients with refractory dyspnoea. A Cochrane review(118) found there was limited evidence for or against benzodiazepine use in refractory malignant or non-malignant dyspnoea, and supports its use if other first line treatments have failed. Cough is also a common symptom in patients with MPM. Chronic cough resulting from disease progression are managed with opioid based anti-tussive (including morphine, codeine) (119) however there are limited high-quality studies investigating this.
Recommendation for Palliative Care in Low Resource Settings
Effective palliative care is essential in the management of MPM. Pain, dyspnoea, and cough are the most common physical symptoms caused by MPM that can be managed through a combination of non-pharmacological and pharmacological interventions. Despite barriers to access specialist palliative care services and appropriate pharmaceuticals and equipment in low-resource settings, international guidelines suggest community health care workers can be trained, empowered, and supervised to delivery safe, appropriate and effective palliative care.
Novel Treatment Options
Newer therapy options have garnered much interest. Recent developments have established the role of immune checkpoint inhibitors (ICI) in the treatment of MPM Where resources allow, the use of ICI should be considered, particularly in those with a sarcomatoid subtype of MPM. ICI however remain costly and are inaccessible for many.
The WHO MLEM added ICI in 2019 for the treatment of metastatic melanoma (nivolumab or alternatively pembrolizumab). The cost of medications is only one of many challenges in the treatment of cancer patients in developing nations, which may include systemic issues such as limited numbers of trained health professionals and late presentations with cancer. Other novel treatment strategies such as photodynamic therapy, gene therapy, CAR-T and tumour treatment fields remain only available in trial settings.
Immunotherapy
Studies of single-agent ICI in the second-line treatment of MPM has not demonstrated significant clinical benefit in trial settings. PD-(L)1 inhibitors have shown response rates between 10-29% in Phase II trials(120-127), with a wide range reported in progression free survival and OS. Survival benefit over standard second-line options has not been demonstrated in randomised Phase III trials. For example, he PROMISE-Meso(128) trial failed to demonstrate superior survival benefit of pembrolizumab (PD-1 inhibitor) over second line chemotherapy (gemcitabine or vinorelbine). The phase IIb DETERMINE trial(126) also did not show survival advantage of tremelimumab (CTLA-4 inhibitor) over placebo in the second or third line.
The combination of CTLA and PD-1 blockade has recently emerged as a new first line treatment option in patients with MPM. The CHECKMATE-743(129) trial is a large phase III trial which randomised 605 patients to pemetrexed with cis/carboplatin or combination immunotherapy (nivolumab and ipilimumab). Interim analysis presented in August 2020 has demonstrated OS advantage of dual immunotherapy over standard cisplatin and pemetrexed chemotherapy (18.1 versus 14.1 months, HR 0.74 [0.60-0.91], p=0.002). Benefit was particularly seen in the non-epithelioid subgroup and in those with PDL1 expression 1%.
Other trials combining standard chemotherapy with immunotherapy with/out anti-angiogenic agents are in progress.
Table 6: Key Immunotherapy Trials
Note:
cis = cisplatin,carbo = carboplatinpem= pemetrexed, gem = gemcitabine, vino = vinorelbine, bev = bevacizumab, nivo = nivolumab
Recommendation for New(er) Treatments in Low Resource Settings
• In low-resource settings, the availability of newer treatments and trials may be limited. If accessible, ICI could be considered in the palliative treatment of MPM.
• Other novel treatment strategies such as photodynamic therapy, gene therapy, CAR-T and tumour treatment fields remain only available in trial settings.
Gene Therapy
Gene therapy involves the transfer of genetic material (such as complementary DNA, genes, RNA or oligonucleotides) into cancer cells via engineered viruses. Several different approaches have been studied in MPM including delivery of cell ‘suicide’ genes, tumour suppressor genes and genes to modulate immune response. Gene therapy is mostly studied in pre-clinical or phase I settings.
For further reading see References 143-150
Photodynamic Therapy
Intra-cavitary photodynamic therapy (PDT) has been investigated as an adjuvant local therapy in surgically resected mesothelioma. An intravenous photo-sensitiser is administered prior to planned EPP or pleurectomy/decortication. After maximal surgical resection, the pleural cavity is treated with laser calibrated to a particular wavelength (nm) and light dose (J/cm2) Although early studies were promising, two small, phase III studies have shown mixed results. PDT has not entered wider use and is recommended (135) only to be utilised in experienced cancer centres, preferably in the setting of a clinical trial.
For further reading see References 151-160
CAR-T Cells
One investigative approach of harnessing the immune system in treating cancer is the administration of tumour antigen-targeted T cells that are engineered to directly target tumour cells. A chimeric antigen receptor (CAR) typically contains an extra-cellular, antigen-recognition domain, a transmembrane domain and an intracellular domain that contain three immune receptor tyrosine-based activation motifs. The CAR is transfected into autologous T-cells via mRNA or viral transduction(136, 137). CAR-T cells have been used in haematological malignancies with promising results, however, face many challenges in solid tumours. In MPM, several potential tumour-antigen targets have been identified such as MSLN, WT-1, FAP and antigens of the ErbB family. As a therapeutic strategy for MPM, CAR-T cells are only available in pre-clinical/early clinical trials.
For further reading see References 161-166
Tumour Treating Fields
Tumour Treating Fields (TTF) are a non-invasive, regional treatment for solid tumours(138) which involves the delivery of low-intensity alternating electric fields to the region of known tumour and has been studied as an adjuvant treatment for brain tumours(139). TTF have been shown to disrupt the assembly of the mitotic spindle essential for mitosis and also to change cellular membrane structures in glioblastoma cell models, potentially increasing permeability to chemotherapy(140, 141). TTF have recently been Food and Drug Administration (FDA) approved for the treatment of mesothelioma based on a single-arm, phase II study(142) which applied TTF during standard first line chemotherapy with cis/carboplatin and pemetrexed. This study had encouraging survival results and no increase in systemic toxicity. This treatment modality requires further investigation in larger trials.
For further reading see References 167-170
