3.1 Treatment of Mesothelioma

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.