**9. Radiotherapy**

Radiotherapy has been studied in three roles for the management of mesothelioma: the palliation of symptoms, prevention of tract site metastases and with radical intent to improve survival alone or as part of multimodality treatment. The first of these was covered earlier and we will focus our discussion here on the other two roles.

#### **9.1. Prophylactic irradiation**

Mesothelioma has been known to seed along interventional tracts to form painful subcutane‐ ous nodules and radiotherapy is commonly used in the prevention of such metastases. In general, the more invasive the procedure, the higher the likelihood is of getting tract metastases [180]. The carte blanche to give prophylactic irradiation came from a randomised trial in 1995 [181]. Boutin et al. randomised 40 patients following thoracoscopy to local irradiation with 21Gy of 12.5-15 MeV electrons in 3 fractions within 15 days of the procedure. They found an incidence of subcutaneous nodules of 40% in the untreated patients and 0% in the irradiated patients. Since then, prophylactic irradiation of intervention sites has become entrenched in guidelines [182] [183] and clinical practice [184] [185].

Two subsequent randomised trials found an incidence of subcutaneous nodules of only about 10% of patients, and that prophylactic irradiation offered no protection against the develop‐ ment of these nodules [186] [187]. The interpretation of these results was confounded by different radiotherapy techniques in these trials [188]. Bydder et al. employed a single fraction of 10Gy of 9MeV electrons delivered up to 15 days following intervention, and O'Rourke employed 21Gy in 3 fractions of 9-12 MeV electrons up to 21 days following intervention. Furthermore, all three trials were underpowered, and in none of them was histological confirmation of subcutaneous nodules obtained.

Further questions which confuse the issue for prophylactic irradiation included the degree to which these nodules are symptomatic - reports varied between 25% and 75% [187] [189], and to what degree these nodules impact on the quality of life of patients. To illustrate the confusion and debate surrounding the use of prophylactic irradiation, we need look no further than the evidence-based guidelines. The latest British Thoracic Society guideline continue to recommend prophylactic irradiation [190], whilst the European Society of Medical Oncology and the European Respiratory Society were not able to recommend it [191, 192]. In the penumbra of all this equipoise, a new randomised trial is being conduct‐ ed to assess the role of prophylactic irradiation in the modern era of chemotherapy, in an adequately powered multicentre study [193].

quent series together corroborated the findings of a relationship between pulmonary compli‐ cations and V20 [205] [206] [207]. As it stands, there is no evidence for additional benefit from IMRT, whilst there are significant concerns about harm. IMRT has not replaced conventional

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Historically, EPP has been reserved for patients who are fit to undergo pneumonectomy, whilst patients who are less fit and/or have unresectable disease are often offered radical pleurecto‐ my/decortication (P/D). However, despite this strategy, patients who underwent EPP not only have a survival advantage over those who underwent P/D, but actually had more morbidity, mortality and worse survival [208]. In recent years, the enthusiasm for EPP has waned and many surgeons has shifted to offering the less morbid P/D, to the extent that the proposed MARS2 trial intends to abandon EPP and instead randomise patients between radical P/D and

The implication this has on delivering radiotherapy within multimodality therapy is signifi‐ cant. Whilst local control becomes even more pertinent, the risk of radiotherapy is also higher because of toxicity to the unresected lung. With the poor results of single modality radical radiotherapy, there is little experience of radiotherapy after pleurectomy-decortication. Some groups have delivered prophylactic radiotherapy to the surgical wounds with occasional boost radiation to at-risk areas, and therefore although described as trimodality therapy, these

When higher dose external-beam radiation was used after pleurectomy-decortication, there was significant treatment-related mortality and morbidity. Likewise, the addition of intrao‐ perative brachytherapy to the pleural space was associated with worse, not better survival. Nevertheless, there was some suggestion that delivery of >40 Gys was associated with better outcome although there is inevitably selection and immortal time bias [211]. There has been interest therefore in the use of IMRT after pleurectomy-decortication to improve delivery of therapeutic doses to disease area whilst keeping normal tissue irradiation to a minimum. Planning is challenging, and for MPM requires over 20 planning cycles. A phase I study found IMRT up to 50Gy was feasible but severe pneumonitis occurred in 20% patients. The median survival of 26 months after receiving all three modalities was comparable to the results after

In conclusion, MPM is an aggressive malignancy which presents insidiously, is difficult to diagnose and is resistant to most standard treatments. There have been a lot of developments over the years but the prognosis remains bleak. A number of ongoing current trials are looking to refine the treatment of this cancer, but it will probably take a quantum leap in thinking to

studies did not reflect the radical doses resembling that after EPP [210].

radiotherapy and its use should be confined to carefully monitored clinical trials.

no surgery [209].

trimodality treatment with EPP [212].

really make a dent in the outcomes.

**10. Conclusion**

#### **9.2. Radical radiotherapy**

Radiotherapy has been used both alone and as part of trimodality therapy in the radical treatment of MPM. A number of trials in the 1980's examined the use of radiotherapy alone with radical intent and found no survival benefit [194]. The use of radiotherapy for mesothe‐ lioma is complicated by the extensive field which it is required to covered, but at the same time juxtaposition of vital structures such as lung, oesophagus, spine, heart, liver and kidneys which limits the dose that can be delivered. Following irradiation of the hemithorax for mesothelio‐ ma, the loss of lung function is complete and equivalent to a pneumonectomy [195]. There is a real risk of treatment-related deaths, reaching 2 out of 12 in one retrospective series [196]. Because of this, it is felt radical radiotherapy should be delivered only after extrapleural pneumonectomy, to avoid the morbidity and mortality associated with life-threatening toxicity to the in-field ipsilateral lung.

The local relapse rate following surgery alone is 70-80% [105], and the focus of radiotherapy has shifted over the years to improving local control within the model of multimodality treatment. However, the rate of local recurrence from single modality radical treatment 53% [197], 35% [198] and 11% [199]. There is a suggestion of a dose-response relationship between radiation dosage and local recurrence but this has not yet been established [199] [200]. Beyond these observational series there is no randomised evidence yet to support or refute the use of postoperative radiotherapy. A multicentre randomised trial for radiotherapy within trimo‐ dality therapy is currently recruiting, but the trial will reach completion only in late 2017 [201]. At present, it is common to include postoperative hemithoracic irradiation to 54Gy within trimodality therapy.

With the tumour abutting a number of radiosensitive vital structures, there has been great interest in the use of intensity-modulated radiotherapy (IMRT) to deliver radiation in a field which conforms much more tightly to the target volume, in an effort to improve delivery to the tumour whilst reducing bystander irradiation. It is much more complex to deliver and requires significantly longer planning and treatment times. Whilst there is a growing body of evidence in support of the benefits of IMRT in various cancers, its use in mesothelioma appears to be harmful. In a series from Boston, fatal pneumonitis in the remaining lung occurred in 6 of 13 patients [202], whilst in MD Anderson, 23 of 63 patients died within 6 months of IMRT, of which 6 were from pulmonary causes [203]. The factor which predicted pulmonary complications appeared to be V20 (volume of lung receiving over 20Gy irradiation) [204]. At the same time, however, the locoregional failure rate remained at 13% [203]. Several subse‐ quent series together corroborated the findings of a relationship between pulmonary compli‐ cations and V20 [205] [206] [207]. As it stands, there is no evidence for additional benefit from IMRT, whilst there are significant concerns about harm. IMRT has not replaced conventional radiotherapy and its use should be confined to carefully monitored clinical trials.

Historically, EPP has been reserved for patients who are fit to undergo pneumonectomy, whilst patients who are less fit and/or have unresectable disease are often offered radical pleurecto‐ my/decortication (P/D). However, despite this strategy, patients who underwent EPP not only have a survival advantage over those who underwent P/D, but actually had more morbidity, mortality and worse survival [208]. In recent years, the enthusiasm for EPP has waned and many surgeons has shifted to offering the less morbid P/D, to the extent that the proposed MARS2 trial intends to abandon EPP and instead randomise patients between radical P/D and no surgery [209].

The implication this has on delivering radiotherapy within multimodality therapy is signifi‐ cant. Whilst local control becomes even more pertinent, the risk of radiotherapy is also higher because of toxicity to the unresected lung. With the poor results of single modality radical radiotherapy, there is little experience of radiotherapy after pleurectomy-decortication. Some groups have delivered prophylactic radiotherapy to the surgical wounds with occasional boost radiation to at-risk areas, and therefore although described as trimodality therapy, these studies did not reflect the radical doses resembling that after EPP [210].

When higher dose external-beam radiation was used after pleurectomy-decortication, there was significant treatment-related mortality and morbidity. Likewise, the addition of intrao‐ perative brachytherapy to the pleural space was associated with worse, not better survival. Nevertheless, there was some suggestion that delivery of >40 Gys was associated with better outcome although there is inevitably selection and immortal time bias [211]. There has been interest therefore in the use of IMRT after pleurectomy-decortication to improve delivery of therapeutic doses to disease area whilst keeping normal tissue irradiation to a minimum. Planning is challenging, and for MPM requires over 20 planning cycles. A phase I study found IMRT up to 50Gy was feasible but severe pneumonitis occurred in 20% patients. The median survival of 26 months after receiving all three modalities was comparable to the results after trimodality treatment with EPP [212].
