MPM remains a hard-to-treat tumor entity lacking evidence-based, standardized guidelines on therapeutic management in the locally advanced setting. We here retrospectively assessed the safety and outcome of MPM treatment with IG/IMHT in a single-center approach, reporting tolerable toxicity as well as promising LC and OS, wherein additional adjuvant chemotherapy was associated with improved outcome.

RT is an established and safe procedure for palliative management of pain or obstruction in localized MPM [18, 19]. However, adequate dose delivery to the target volume in curative intent has been a major challenge for radiation oncologists for a long time and indications for RT must be well defined, taking into account treatment-related side effects. A randomized controlled phase III trial previously assessed routine irradiation of the surgical procedure tract, which was not included in the target volume in this collective, observing no significant benefit regarding local procedure tract metastases but also quality of life at the expense of increased early postinterventional toxicity [20]. The introduction of IMRT defined a new era, as it allows safe and effective curative-intent dose delivery to the MPM while sparing OARs sufficiently [15]. Adjuvant RT after P/D is particularly challenging as the lungs remain in situ and, thus, sparing of these OARs complicates dose delivery to the target volume. Ironically, this renders extensive and complicated surgery with radical EPP the easier approach for radiation oncologists. We have previously demonstrated the feasibility of adjuvant curative-intent RT after P/D with HT-based planning, thus improving potential lung and kidney sparing [17]. Although both HT (Fig. 3) and VMAT may provide very satisfying and comparable dose distributions, there are distinct characteristics and advantages for both treatment techniques. In our previous series, HT achieved optimal contralateral lung sparing, which may be considered the priority planning objective due to the relevant risks of impairing quality of life and potentially lethal events following pneumonitis. We also reported slightly superior target volume coverage for HT, but its clinical significance remains unclear. On the other hand, HT usually necessitates significantly longer beam-on time. Ultimately, the RT technique of choice requires consideration of individual patient-centered factors like clinical performance and compliance to patient positioning or breath-holding, and physical factors like the geometry of the designated target volume and adjacent anatomy.

Exemplary illustration of target volume delineation (a) and dose distribution (b) with helical tomotherapy in a 60-year-old female with epitheloid malignant pleural mesothelioma receiving 1.8 Gy to 50.4 Gy following neoadjuvant chemotherapy (cisplatin and pemetrexed) and extended pleurectomy/decortication. CTV clinical target volume, PTV planning target volume

While systemic chemotherapy is an established approach to improve both PFS and OS for MPM not eligible for curative surgery [21], the true prognostic role of both chemotherapy and RT in localized MPM remain undisclosed [22, 23]. This is mainly due to low overall patient numbers, but also a high clinical heterogeneity within the MPM patient collectives, which hampers patient recruitment for randomized trials. As such, even though IMRT has already become standard of care in developed countries [24], there are only limited data on its effect on RT outcomes in MPM thus far. Most available data focus on post EPP-RT. EPP is the most radical surgical option for localized MPM, which requires careful patient selection and is associated with severe toxicity [9]. Patients undergoing this extensive surgery may suffer from impaired mobility and overall reduced quality of life. While P/D was formerly considered a purely palliative procedure, recently, various studies have established a curative role for the procedure [7], making it the primary option for sensitive multimodal treatment building up on the advances in RT technology allowing for more precise, dose-escalated RT. In fact, our results are in line with previous reports on IMRT of MPM after EPP (Table 3), although all our patients received less extensive, lung-sparing surgery or no surgical resection at all. Besides the mentioned primary patient-centered benefits with reduced risk of mortality, toxicity, and in-hospital times, our results also suggest a treatment option which spares the limited economic resources and capacities of the health care system [25].

With the ongoing implementation of next-generation O‑ring linear accelerators into clinical practice, interest has increased in experiences with last-generation HT [26]. First reports on palliative HT of MPM suggest good efficacy at low toxicity [27]. Only a very small series of 10 patients [28] has previously assessed the role of IMRT HT for P/D patients, reporting an excellent toxicity profile. In the largest retrospective EPP series to date, Thieke et al. reported a 1-year OS of 63% [2], which was exceeded by far in this series with 86%. However, 2‑year OS was similar, with 42% each. Of note, we observed a very high LC rate of 92.6% after 1 year, which may have contributed to the improved overall outcome. The convincing DC rate of this series is most likely due to the systemic chemotherapy, as adjuvant chemotherapy was associated with a significant OS improvement. The described outcome benefit of trimodal MPM treatment is consistent with other reports [11, 29].

Given the acceptable toxicity profile of IMRT reported here but also elsewhere [2, 14, 30, 31], it remains debatable whether MPM patients might furthermore benefit from applying a sequential boost [29, 32]. In comparison to older studies incorporating outdated RT techniques with fatal events [33], the reported toxicity profile clearly demonstrates the benefit of modern RT techniques, as no grade 4 or 5 events were recorded. Nevertheless, the grade 3 toxicity rate of more than 25% presented here has to be taken into account in patient counseling and clinical decision-making, as meticulous patient selection for this intensive treatment regimen remains crucial. Additionally, as yet widely unestablished standardized patient monitoring and early management of occurring side effects may alleviate symptom burden and prevent high-grade toxicity [34, 35].

Our study has several limitations. The small sample size did not allow for a more detailed analysis of prognostic factors or stratification such as patients receiving trimodal treatment versus RT or chemotherapy only. Equally, the long interval between the first and last patients included may cause a bias due to the heterogeneity in care patterns. However, MPM is a rare disease and clinical outcome reports of RT are scarce. To the best of our knowledge, this is one of the largest cohorts reported thus far accounting for technical progress that has been made recently. More importantly, this is the first report on the safety and outcome of IG/IMHT of MPM with a relevant patient number.

Due to the lack of randomized clinical trials, the debate on the optimal treatment pattern for locally advanced MPM is likely to continue. A single-center phase II trial recently reported convincing long-term outcomes for neoadjuvant IMRT followed by EPP at the costs of high toxicity [39]. An ongoing phase III randomized clinical trial may soon shed some light on the optimal treatment pattern for locally advanced MPM [40].