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Overview of treatment
Malignant Pleural Mesothelioma (MPM) is an aggressive malignancy that arises from the mesothelioma surfaces of the pleural cavity. Predominately associated with asbestos, this illness is diagnosed often many decades after initial exposure. Despite legislation against the use of blue asbestos in 1978, and an Australia wide ban on chrysotile asbestos in 2003, Australia is only now seeing evidence of an incidence peak. Furthermore, ongoing exposure to asbestos in the domestic setting, particularly amongst tradesmen and home renovators, will see ongoing diagnoses of this malignancy for decades to come. In the developing world, where significant ongoing industrial and household use of asbestos remain MPM, amongst other asbestos related diseases (ARDs) will continue to surge.
A practical approach to the management of MPM is required encompassing systemic therapy, radiation therapy, surgical intervention and palliative care.is essential. We highlight current best practice and the evidence supporting the use of anti-cancer and supportive therapies, acknowledging the ‘gold standard’ for optimal care in addition to realistic and feasible interventions that are recommended in resource-poor regions.
Systemic therapies have an important role in the management of unresectable malignant mesothelioma. Since 2003, several large randomised trials have reported survival benefit and improved quality of life (QoL) with the use of cisplatin and pemetrexed in MPM, which is now considered the standard of care in those with good performance status and adequate organ function (1) Carboplatin in combination with pemetrexed is a reasonable alternative- especially for those who are older or with co-morbidities precluding use of cisplatin. Few alternative systemic treatment options yield response rates exceeding 20% in phase II trials (2).
Combination Chemotherapy with Cisplatin (or Carboplatin) and Pemetrexed
The current standard of care for MPM was established following the results of a large phase III trial by Vogelzang et al. in 2003, which compared combination chemotherapy with cisplatin and pemetrexed, with vitamin B12 and folate supplementation (1). In this trial, 456 chemotherapy-naïve patients with MPM were randomized to cisplatin (75 mg/m2) and pemetrexed (500 mg/m2) given every 3 weeks, or cisplatin alone. Those receiving cisplatin and pemetrexed had a longer median OS (12.1 vs 9.3 months, p=0.02), longer time to progression (5.7 vs 3.9 months p=0.001) and higher objective response rate (41 vs 17%, p<0.0001) compared to cisplatin alone. Those who were also supplemented with oral folic acid and intramuscular vitamin B12 had improved survival, less treatment-related haematological toxicity and received a greater mean number of cycles of treatment.
Quality of life and symptoms were also assessed through the LCSS-Meso questionnaire which had been previously validated MPM (3). Patients who received the combination treatment had statistically significant improvements in symptoms (pain, cough, dyspnoea) by cycle 4, and global QoL and fatigue by cycle 6 (4). Analysis from this trial also identified good performance status, early disease stage, epithelioid histological subtype and non-elevated total white cell count as independent prognostic factors.(5)
Carboplatin is a reasonable alternative for cisplatin in combination with pemetrexed in patients with contraindications to cisplatin. Outcomes for patients who received pemetrexed (500mg/m2) in combination with cisplatin (75mg/m2) or carboplatin (AUC 5) were similar in those enrolled into the International Expanded Access Program(6). Median time to progressive disease was 7 vs. 6.9 months, 1 year survival rates were 63.1% vs 64% and overall response rates 26.3 vs 21.7%.
There have also been three non-randomised Phase II trials evaluating the role of carboplatin and pemetrexed in patients with MPM. Median OS in these three trials range between 12.7 – 14 (7-9). A combined analysis of two of these trials found that the combination of carboplatin and pemetrexed was well tolerated and had similar efficacy in elderly patients (>70 years) compared with younger patients with MPM (10).
Duration and Timing of Chemotherapy
The optimal duration of treatment has not yet been defined, but a commonly used standard for first-line treatment of patients receiving cisplatin (or carboplatin) and pemetrexed is a maximum of six cycles. The median number of cycles of cisplatin and pemetrexed in the seminal Vogelzang et al. 2003 was six, with only 5% of patients tolerating ³ 8 cycles. There is no randomised evidence to show that four cycles of chemotherapy are sufficient.
The feasibility of maintenance pemetrexed after induction chemotherapy was explored in a small non-randomised study in 2006(11). This study found good tolerability of maintenance pemetrexed, with low rate of Grade 3 or 4 toxicities, however was underpowered to investigate treatment response or patient survival.
Following this, a randomised phase II study(12) administered maintenance, single agent pemetrexed vs. observation until disease progression after 4-6 cycles of combination pemetrexed with platinum chemotherapy. Patients in the treatment arm received a median of 4 extra cycles of pemetrexed until disease progression – however, there was no benefit in median progression free survival (median 3.0 vs 3.4 months, HR 0.99, CI 0.51-190, p = 0.9733), nor OS (11.8 vs. 16.3 months, HR 0.86, CI 0.44-1.71, p = 0.6737). Therefore, maintenance pemetrexed is not part of standard clinical practice for MPM.
The timing to start palliative chemotherapy is important as the clinical course of patients with mesothelioma varies widely from indolent to rapidly progressive disease. It is reasonable to consider a period of careful observation with clinical and radiological review before commencing palliative systemic therapy in asymptomatic patients with good prognostic features including epithelioid histology subtype and low tumour volume.
There has been one randomised study of chemotherapy delivered at diagnosis or delayed until symptomatic progression in MPM. This underpowered trial did not show statistically significant difference in OS (14 vs 10 months, p=0.1) nor difference in QoL or symptom outcomes (13). It is important to note that the chemotherapy used in this study (mitomycin, vinblastine and cisplatin) is no longer considered standard of care treatment.
Alternative Cytotoxic Regimens
There are few effective alternative options to first line combination cisplatin (or carboplatin) and pemetrexed chemotherapy. The combination of cisplatin with raltitrexed or gemcitabine could be considered only if pemetrexed was contraindicated or unavailable.
A randomised phase III trial by van Meerbeeck et al. in 2005 compared cisplatin (80mg/m2) alone, or in combination with raltitrexed (3mg/m2) in 250 chemotherapy-naïve patients with MPM. In this trial, median OS was reported to be improved significantly (11.4 vs 8.8 months p=0.048), and higher response rates (24 vs. 14%, p=0.06). The difference in progression free survival was not statistically significant (5.3 vs 4 months(14).
The combination of cisplatin and gemcitabine has been evaluated in several small phase II trials as first-line combination chemotherapy for MPM. Reported response rates ranged from 12-48% and median OS 9.5-12 months (15-19). The combination of carboplatin and gemcitabine has also been evaluated in a multi-centric Phase II study (20) with comparable response rate (26%) and median survival (66 weeks) to combination with cisplatin.
Treatment of Relapsed Mesothelioma (2nd line treatment and beyond)
Many patients with MPM who benefit from first line treatment are still relatively fit at time of radiological disease progression and potentially could receive further treatment. Chemotherapy beyond first line treatment is less well-studied and the optimal regimen is unknown. In developing nations where availability of first line agents is limited, suitable second line options remain minimal.
Pemetrexed Naive, but Previously Treated Patients
In previously treated, but pemetrexed-naïve patients with relapsed MPM, a pemetrexed containing regimen should be considered in the second-line.
An observational study by Janne et al. (2006) reported outcomes of 153 pemetrexed naïve patients with MPM who received pemetrexed based chemotherapy via an access program in the second line setting(23). Patients receiving combination pemetrexed plus cisplatin or pemetrexed alone had similar rates of stable disease (36.3% and 41.1%, respectively), however higher rates of treatment response occurred in those receiving combination therapy (32.5%, compared with 5.5% for single-agent pemetrexed).
These findings were confirmed in a phase III trial by Jassem et al. (2008) (24) comparing pemetrexed 500mg/m2 and best supportive care (BSC) with BSC alone in 243 patients with previously treated but pemetrexed-naïve patients with relapsed MPM. Response rate significantly favoured the pemetrexed arm (18.7 vs 1.7%, p<0.001) and median PFS was also longer in the pemetrexed arm (3.7 vs 1.5 months, p=0.0148). There was no statistically significant difference in QoL assessments nor in OS (8.4 vs 9.7 months, p=0.0148) - although these may have been confounded by the significant proportion of patients receiving chemotherapy after trial discontinuation (35% in pemetrexed arm vs. 51.7% in BSC arm).
Zucali et al. 2011(25) published a retrospective of 423 patients who received second line treatment for MPM between 1996-2008. With second line treatment, 52.6% achieved disease control, median PFS 4.3mo, OS 8.7 months. According to multivariate analysis, disease control after second line therapy was related significantly to pemetrexed based therapy (OR 2.46, p=0.017), and time to progression of greater than 12 months from first line therapy (OR 3.5 p=0.006). The progression free and OS was also related to time to progression of greater than 12 months after first line therapy (HR: 0.45; p<0.001 and HR: 0.54; p=0.005 respectively) and ECOG PS 0 (HR 0.67, p=0.022, HR: 0.43; p<0.001 respectively). In those previously exposed to pemetrexed, retreatment with a pemetrexed and platinum combination significantly reduced the risk-of-death than pemetrexed alone (HR: 0.11; p<0.001).
Rechallenge with Pemetrexed
A rechallenge with a pemetrexed-containing regimen could be considered in the second line if there was durable period of stable disease or response to treatment in the first line.
In an observational study by Ceresoli et al (2011) (26), 31 patients received pemetrexed based therapy as second line (18/31) or beyond second line treatment (13/31). Patients had at least 3 months of non-progressive disease after treatment with previous treatment with pemetrexed based regimens. The objective response rate was 19%, and a further 29% had stable disease. Whilst in the overall population, the median progression free survival (PFS) was 3.8 months and OS 10.5 months, patients with a first-line progression free survival of greater than 12 months had a longer median PFS after re-treatment (5.5 vs 2.5 months) when compared to patients with a shorter first line progression free survival.
These findings were similar to those found by Bearz et al (2012)(27) in a multi-institutional setting. Best response was stable disease in 50% of patients, partial response in 17% and reduction of pain was noted in 43%. Median time to progression on re-treatment was 5.1 months. There was no difference between time to progression of the group receiving pemetrexed alone or in combination with a platinum (4 vs. 5.7 months, p=0.77).
Other Single-Agent Chemotherapy Regimens
Single-agent chemotherapy regimens have been studied in Phase II studies with limited success. These would only be considered an option in patients who progress during first-line treatment with a pemetrexed based regimen, or where response to treatment is short, and no other effective treatment options are available.
Vinorelbine has been evaluated in small, non-comparative Phase II trials in the second line after previous treatment with a pemetrexed based regimen(28, 29). Reported response rates (partial at best) were 7-15%, with progression free survival of 2.3-2.5 months and OS of 4.5-6.2 months. In one study (28), factors such as ECOG performance status (PS) (0 vs. 1-2) HR 0.50; 95%CI: 0.3-0.8; p = 0.014) and PFS ≥ 6 months following first-line (FL) chemotherapy (HR(FL-PFS>6 months vs. <6 months) 0.50; 95%CI: 0.3-0.9; p = 0.031) were significantly associated with improved OS in multivariate analysis.
Gemcitabine alone has yielded disappointing response rates and overall median survival <5 months(30). A combination of both gemcitabine and vinorelbine has been studied in small, single-arm phase II studies (31, 32) with only modest efficacy and is not recommended as standard treatment.
MPM cell lines express several angiogenic factors including members of the vascular endothelial growth factor (VEGF) family and its two receptors (VEGFR1 and VEGFR2). VEGF signalling can induce autocrine growth in malignant mesothelioma cells and have shown sensitivity to anti-VEGF agents in vitro (33, 34). Although there is strong rationale for inhibiting angiogenesis, few trials of anti-angiogenic agents in MPM have yielded positive results.
Bevacizumab is an anti-VEGF recombinant humanised IgG1 antibody derived from the murine monoclonal antibody A4.6.1. bevacizumab hampers the ability of VEGF to bind to VEGF receptors on the surface of endothelial or mesothelial cells and inhibit VEGF induced proliferation. The addition of bevacizumab to combination of cisplatin and pemetrexed has been trialled with statistically significant but small additional survival benefit (16.1 vs 18.8 months, HR 0.77 [0.62-0.95], p=0.0167) and expected added toxicities(35). Bevacizumab is not approved for use by the FDA. Therefore, due to significant out of pocket costs, it is not widely used and in many settings is not considered part of standard of care treatment.
Other antiangiogenesis agents however have proven less promising with both thalidomide and nintedanib failing to demonstrate clinical benefit.
Recommendation for Systemic Treatment in Developing Nations
The availability and accessibility of systemic treatments varies widely between and within developing nations. Therefore, where available, the first-line systemic therapy for MPM should be combination chemotherapy with cisplatin (or carboplatin) with pemetrexed. The World Health Organisation (WHO) Model List of Essential Medications (MLEM) (42) outlines the minimum medications needed for a basic health care system, listing the most efficacious, safe and cost effective pharmaceuticals for priority conditions, based on current and future public health relevance. This list includes both carboplatin and cisplatin for the treatment of non-small cell lung cancer. Although pemetrexed is not included, it is a reasonable expectation that its cost and availability will improve in future. The list also includes gemcitabine and vinorelbine for the treatment of non-small cell lung cancer, which are also second line options in MPM. Although the WHO MLEM does not specifically include drugs for the treatment of mesothelioma, it would suggest that these chemotherapy agents may be available in low-resource settings.
Where systemic therapies are not accessible, the recommended approach is best supportive care, focussing on palliation of symptoms and management of pleural effusions. Clinical trials are less available in developing nations and therefore experimental therapies or treatments with less evidence-base are not generally recommended. Biological agents (such as bevacizumab) and immunotherapy should be considered in centres with appropriate expertise and resources.
Most patients with MPM present with advanced disease and associated symptoms. While MPM is generally considered to be radio-resistant, radiotherapy is a useful treatment modality in palliating symptoms of MPM, especially pain. The delivery of radiotherapy in MPM is technically challenging due to complex tumour shape, burden of disease, respiratory motion and surrounding radio-sensitive structures. Advanced conformal and intensity modulated techniques have been helpful in the safe delivery of appropriate doses of radiation.
For the role of radical radiotherapy as part of trimodality therapy see Section: Surgical Interventions and Palliative Procedures.
Radiation can be useful in the palliative management of MPM, particularly in pain management . Single centre studies of the use of radiotherapy for pain management caused by MPM have reported 47-65% of recipients experiencing benefit (43-48). No randomised trials or systemic reviews have demonstrated an survival advantage with the use of palliative radiotherapy (49, 50).
The prospective multicentre phase II SYSTEMS trial(43) assessed responses to pain at 1, 5 and 12 weeks following palliative radiotherapy (20Gy in 5 fractions) to painful chest lesions in patients with MPM. Of those assessable at the 5-week mark, 47% were reported to have improved pain. There were no improvements in symptoms other than pain (such as dyspnoea, fatigue, sweats, anxiety and depression) and minimal treatment-related toxicity. Another retrospective study by Jenkins et al(46) found that 57% of the studied cohort reported improvement in pain post-radiotherapy. In this study, response to treatment correlated with EORTC prognostic index (p=0.001), performance status (p=0.001) and histological subtype (0<0.001). A study by Bissett et al(48) suggested that wide-field radiotherapy (30Gy in 10 fractions) of the affected hemithorax was well tolerated, and most participants (68%) experienced symptom benefit after 1 month. The effect, however, was not long-lived with most (75%) patients reporting worsening pain at 3 months.
The optimal dose and fractionation is yet to be defined, however international guidelines(45) suggest standard palliative dosing regimens (such as single fraction of 8Gy) for MPM, although higher cumulative dosing and higher dose per fraction could be used to improve symptomatic response. There has been a prospective trial(51) of high dose palliative radiotherapy (45-60Gy using conformal and intensity-modulated techniques) which yielded significant excess toxicity without additional symptomatic benefit or survival. Researchers await the results from the SYSTEMS-2 trial(52), which is a randomised phase II trial comparing a standard regimen (20Gy in 5 fractions) with a dose-escalated regimen (36Gy in 6 fractions) for pain control in MPM. Currently, high dose radiotherapy with palliative intent remains outside of standard practice.
Radiotherapy to Prevent Instrumentation Tract Metastasis
Anecdotal concerns for patient with MPM regarding the potential for tumour seeding with instrumentation of the pleural space may result in a reluctance of clinicians to appropriately perform simple diagnostic or therapeutic procedures involving the pleura, particularly where radiotherapy is not available. It is important to note that the incidence of tract metastasis from large bore procedures in patients with MPM is low. Furthermore, the use of radiotherapy for preventing instrumentation tract metastases in MPM is not standard of care for those undergoing limited diagnostic or therapeutic procedures.
High quality phase III studies have shown no benefit in prophylactic radiotherapy in reducing incidence or improving symptom or QoL outcomes. Three small randomised trials had conflicting conclusions on the efficacy of prophylactic radiotherapy to prevent instrumentation tract metastases (53-55). These were followed by two randomised Phase III studies that showed no benefit of prophylactic radiotherapy in this setting.
The SMART trial(56) was multicentre phase III trial where patients were randomised to receive immediate or delayed radiotherapy (21Gy in 3 fractions) after large-bore pleural interventions such as video assisted thorascopic surgery (VATS), thoracoscopy or indwelling pleural catheter insertion. The overall incidence of tract metastasis was low and the early versus delayed strategy did not produce a statistically significant difference in incidence (9 vs 16%, OR 0.50 [CI 0.19-1.32], p=0.14). Notably, there was also no difference in symptom control, use of analgesia, survival or QoL. A large phase III trial (57) randomised patients to receive no prophylactic radiotherapy or 21Gy in 3 fractions within 42 days after instrumentation. There was no difference observed in the incidence of chest wall metastasis (3.2% vs 5.3%; OR 0.60 [0.17-1.86], p=0.44) between the groups. Careful clinical follow up and ad hoc radiotherapy for chest wall metastasis is recommended over prophylactic radiation.
Recommendations for Radiotherapy in Developing Nations
Radiotherapy can be a useful form of palliative treatment to reduce pain caused by MPM. There is no evidence to show survival benefit or reduction in respiratory symptoms such as dyspnoea or cough with palliative radiotherapy. There is no role for prophylactic radiotherapy to prevent tract metastases after instrumentation of the pleural space. In resource limited settings, radiotherapy may not be readily available or accessible and other available means of palliating symptoms should be explored including pharmacological and non-pharmacological strategies for pain management.
Surgical Interventions and Pallative Procedures
Few patients are eligible for radical surgery performed with curative intent due to extent of disease and functional status. Extra-pleural pneumonectomy (EPP) or extended pleurectomy/decortication (eP/D) have been performed in this setting to achieve maximal macroscopic resection. However, surgery alone has not shown adequate rates of disease control. A combined approach of surgery, chemotherapy and radiotherapy (Trimodality therapy aim to improve locoregional control and survival outcomes. As the majority of patients with MPM present with advanced, unresectable disease, in clinical practice, most surgical procedures are performed for the purposes of palliation and obtaining diagnosis. Partial pleurectomy/decortication is a palliative procedure performed in MPM to improve symptoms related to trapped lung. Pleurodesis is another palliative procedure performed to manage symptomatic, recurrent malignant effusions.
Extra Pleural Pneumonectomy (EPP)
EPP is an aggressive approach to achieve complete cytoreduction in MPM. Despite better rates of macroscopic clearance (58), EPP rarely results in long-term survival despite combination with chemotherapy and/or radiotherapy. Despite the more extensive surgery and potentially higher doses of adjuvant radiotherapy being able to be delivered after EPP (due to absence of ipsilateral lung), locoregional recurrence remain the most common site of treatment failure (59, 60). EPP is considered unsuitable for most patients with MPM due to higher perioperative mortality and post-operative morbidity. It is particularly unsuitable for those with poor prognostic factors (61) including cardiac risk factors, simultaneous N1 and N2 disease (62) and non-epithelioid histology.
The 2018 British Thoracic Society guidelines advises against EPP in any context and eP/D outside of clinical trials. Meanwhile, the ASCO 2018 guidelines recommend radical surgery only in the context of multi-modality treatment (e.g. with neo/adjuvant chemotherapy and radiotherapy). Ultimately, studies of cancer registries in USA and Australia have shown low rates of EPP for MPM (6-8%)(63, 64). As there is no standardised approach to surgery for resectable MPM, radical surgery should only be considered in combination with chemotherapy and/or radiotherapy in highly specialised centres with experience and case-volume in addition to careful patient selection.
A systematic review by Cao et al (8), reviewed 58 studies including 2462 patients from 26 institutions. Median OS ranged from 9.4-27.5 months, with a median disease-free survival ranging between 7 to 19 months. Perioperative mortality rates varied widely from 0-11.8%, with significant perioperative morbidity rates (22-83%) and major morbidity rates (12.5-48%) noted. Only 3 studies looked at QoL, reporting a significant deterioration in QoL scores post-operatively, taking a further 3-6 months before improvement noted.
The 2011 MARS study(65) was undertaken as a prospective, randomised and controlled feasibility study to compare EPP or no-EPP in the context of multimodality therapy. 3 cycles of induction platinum-based therapy (investigator’s choice of mitomycin, vinorelbine and cisplatin, or cisplatin with gemcitabine, pemetrexed or vinorelbine) was given prior to randomisation. This study showed a significant detriment in survival outcomes for those patients undergoing EPP. A reduction in 12-month survival rates (52.2% [30.5-70.0] in the EPP arm vs. 73.1% in the no EPP arm [51.7-86.2]) was identified, and after adjustment for pre-specified prognostic factors, the hazard ratio for survival was 2.75 (1.21- 6.26, p=0.016). Median survival was 14.4 months vs. 19.5 months with no EPP. Investigators concluded that there was no survival advantage of EPP as part of multimodality therapy. Furthermore, as there were concerns regarding peri-operative safety (including a 10.5% 30-day mortality) and overall detriment to survival outcomes, the authors concluded a larger study could not be justified. These findings remain controversial as the MARS1 was criticised for being underpowered and the perioperative morbidity and mortality were higher than other studies reported in the literature. EPP remains utilised by some, and it is postulated that in a highly selective patient population with an experienced surgical team with good case-volume may be critical factors in obtaining optimal results.
Extended pleurectomy/decortication (extended P/D) is performed with curative intent where tumour is resected from the hemithorax including the diaphragm and/or pericardium (as required). The ipsilateral lung is spared. Many centres advocate eP/D over EPP due to lower rates of early complications and mortality, and comparable survival. A direct comparison between EPP and extended P/D is inherently difficult and to date, there have been no prospective randomised trial to compare the two surgical approaches.
A systematic review in 2013 by Cao et al(66) showed that extended P/D was associated with perioperative mortality ranging from 0-11%. Overall perioperative morbidity occurred in 20-43%. The reported median OS ranged between 11.5-31.7 months and disease-free survival between 7.2-16 months.
The largest descriptive case study to date is a retrospective of 663 consecutive patients who underwent EPP or P/D between 1990 and 2006 (67). The results suggested survival benefit in extended P/D, over EPP (p < .001). Multivariate analysis demonstrated a hazard ratio of 1.4 for EPP (p<0.001), after controlling for known factors that influenced survival on multivariate analysis, including AJCC stage (p < .001), epithelioid histology (P < .001), gender (P < .001) and multimodality therapy versus surgery alone (p < .001). The perioperative mortality rate was reported to be higher for EPP than for P/D (7% vs 4%). The authors however emphasised that the result of OS benefit is likely to be multifactorial and subject to patient selection bias. They concluded that resection technique should be based on individual comorbidities and the planned other multi-modal treatments.
Several other studies have reported on QoL and symptom outcomes and are also mostly in favour of extended P/D, mainly due to lower perioperative complications, better long term QoL, and longer survival post recurrence despite similar disease-free survival (68, 69). A randomised study (MARS2) is currently recruiting comparing extended P/D versus no extended P/D, with randomisation for surgical procedure occurring after 2 cycles of neoadjuvant cisplatin and pemetrexed chemotherapy. Study completion is expected in late 2020 and results by 2022. Extended P/D for MPM should only be performed in a carefully selected patient group, in high volume centres with surgeons of considerable experience or in the context of a clinical trial.
In patients with resectable MPM who can be considered for EPP or extended P/D, a combined approach of surgery, chemotherapy and radiotherapy (Trimodality therapy) has been undertaken with the intent to improve locoregional control and survival outcomes. This approach is associated with high risk of treatment-related morbidity and mortality and is therefore recommended only to be performed in select patients in specialised centres with experience and expertise, preferably in the context of clinical trials.
International guidelines currently vary in their recommendations for multi-modal treatment for resectable mesothelioma. Best reported survival outcomes have been reported in series using multi-modal therapy, with median OS reported even up to 46.9 months(70-72). However, there have been no adequately powered randomised trials that have shown benefit of tri-modality therapy over chemotherapy or surgery alone(73). Systematic reviews of multimodality therapy have concluded that the evidence in favour of trimodality therapy over single-modality therapy (i.e. surgery or chemotherapy alone) is weak overall(73-75) and it is therefore paramount to carefully select candidates for trimodality therapy.
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 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.
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 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 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.
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.
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 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
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
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