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Anna Wrona

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    MS 08 - Novel Treatment for Mesothelioma (ID 530)

    • Event: WCLC 2017
    • Type: Mini Symposium
    • Track: Mesothelioma
    • Presentations: 1
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      MS 08.02 - Current Role of RT In MPM (ID 7676)

      15:45 - 17:30  |  Presenting Author(s): Anna Wrona

      • Abstract
      • Presentation
      • Slides

      Local therapy as the primary treatment modality of early malignant pleural mesothelioma (MPM) remains highly controversial due to lack of clear benefit in comparative clinical trials. In specialized experienced centers, the initial approach is usually surgical resection - extrapleural pneumonectomy (EPP) or pleurectomy/decortication (P/D). No consensus exists with regard to the optimal use of radiotherapy (RT) in MPM. At the present time, there is no evidence to support the use of radical RT as a single modality in MPM, because of the inability to deliver a therapeutic high dose of radiation (e.g. 60Gy in 30 fractions) to the entire pleura without overdosing the surrounding organs at risk. However, RT has been used in the management of MPM in three indications: as prophylaxis to reduce the incidence of recurrence and pain at sites of diagnostic or therapeutic instrument insertion, as part of multimodal definitive treatment (following induction chemotherapy and surgical resection) to improve locoregional control in early-stage disease and for palliation of symptoms (mainly chest wall pain) in patients with advanced disease. During thoracoscopy, thoracocentesis or needle biopsy in patients with MPM, the seeding of tumor cells along the needle tract may occur, leading to painful metastases at the intervention sites in 20-50% of cases [1]. Prophylactic radiotherapy to chest wall sites of invasive procedures has previously been recommended. However, recent randomized studies (e.g. SMART trial) have shown that prophylactic RT should not be routinely used to prevent procedure tract metastases (PTMs) in MPM, as it confers no benefits in terms of chest pain control, analgesia use, survival, QoL and the data on the potential effect on PTMs' incidence reduction are discrepant [1]. Instead patients should undergo careful clinical follow-up allowing the immediate detection and treatment of PTMs. Surgical resection alone in early MPM is associated with high local recurrence rates (69% after P/D and 38% after EPP) [2]. Therefore, to reduce local failure rate conventional RT has been used as a component of potentially curative trimodality treatment. Adjuvant RT was first used in patients after EPP and was delivered with anterior posterior photon fields matched with electron boost fields. A similar hemithoracic RT technique was explored after P/D, but additional block for central part of the lungs was required. The population based studies data on the potential role of adjuvant RT in improving overall survival (OS) are conflicting [3]. However, a subsequent analysis utilizing the National Cancer Database (NCDB) revealed the improvement of the 2-year rate of OS from 20% to 34% in patients with MPM receiving conventional RT after surgery [3]. Without significant improvement in local control and overall survival after P/D, conventional RT has been shown to decrease local recurrence after EPP to 13% and result in a median survival of 17 months [3]. The benefit in local control was strongly dose-dependent and obtained with a median dose of ≥54Gy [3]. Subsequently, the IMRT technique was implemented to improve adjuvant RT outcomes after P/D (IMPRINT approach). This novel method offers better coverage of the extensive, irregularly shaped target, safer dose escalation in the target volume and optimal sparing of OARs, but results in more heterogenous dose distribution, with a larger volume of normal tissue receiving low-dose radiation than in conventional techniques. IMRT was shown to be associated with a lower incidence of local recurrence (14% vs 42%), improved overall survival (median 20 vs 12 months) and lower rates of grade ≥2 esophagitis (23% vs 47%) when compared with conventional techniques [4]. A potential disadvantage of IMRT is the dose delivered to the contralateral lung that is associated with higher risk of pneumonitis (up to 46% of fatal pneumonitis in early series) [5]. Mean contralateral lung dose >8,5Gy and higher percentage (>80%) of the contralateral lung receiving dose >5Gy were significantly associated with higher risk of pulmonary toxicity. Strict dosimetric constraints, particularly on the contralateral lung (MLD<8,5Gy, V20<10%, V5<60%) and optimal algorithms in treatment planning (e.g. accurate measurement of volumes receiving low radiation doses on the basis of Monte-Carlo algorithm), are critical for radiotherapy planning [4]. Another novel approach employs the combination of IMRT and electrons, that offers better sparing of heart, liver and kidneys [6]. The technical aspects of adjuvant IMRT for MPM can further be improved. When compared to step-and-shoot linac-based IMRT, the use of helical tomotherapy significantly improved target coverage, homogeneity index, lowered average V5<40% and MLD<5Gy for the contralateral lung [7]. Intensity-modulated arc therapy also demonstrated superior V20 and better target coverage in addition to shorter treatment delivery time [8]. Proton therapy was also evaluated in the mentioned setting, offering better sparing of OARs and possibility of further dose escalation to improve target coverage [9]. Whether these dosimetric advantages will translate into clinical benefit, should be assessed in future prospective studies. The trimodality treatment of MPM consisting of induction chemotherapy (pemetrexed+cisplatin), surgical resection and adjuvant radiation has resulted in the best survival outcome thus far in non-randomized cohorts. Accelerated hemithoracic radiation (25Gy in 5 daily fractions), followed by EPP, was evaluated as an alternative. This approach is feasible and associated with encouraging overall survival (median of 51 months) and disease-free survival (47 months) in patients with epithelial cT1-3N0M0 MPM [10]. These promising results should support further studies to clarify the role of hypofractionated pre-operative RT in the management of MPM. Radiotherapy can provide palliation of chest pain in the course of MPM in 50-60% of cases, although the duration of response is often disappointing (2-3 months) [11]. An effective palliation was observed after the dose ≥40Gy and a higher local response rate for patients treated with a 4Gy per fraction regimen compared with those receiving fractions lower than 4Gy was reported (50% vs 39%) [11]. Many aspects of RT for patients with MPM are still not standardized and warrant further investigations. Clinical trials designs will require integration of new systemic therapies, immune modulation and novel technology advances in RT, with the guidance of predictive and prognostic biomarkers, as well as genetic profiling. MPM patients with resectable disease should be encouraged to participate in clinical trials. Bibliography: 1. Arnold DT, Clive AO: Prophylactic radiotherapy for procedure tract metastases in mesothelioma: a review. Curr Opin Pulm Med 2017, 23(4):357-364. 2. Pass HI, Kranda K, Temeck BK, Feuerstein I, Steinberg SM: Surgically debulked malignant pleural mesothelioma: results and prognostic factors. Ann Surg Oncol 1997, 4(3):215-222. 3. Rosenzweig KE: Malignant pleural mesothelioma: adjuvant therapy with radiation therapy. Ann Transl Med 2017, 5(11):242. 4. Shaikh F, Zauderer MG, von Reibnitz D, Wu AJ, Yorke ED, Foster A, Shi W, Zhang Z, Adusumilli PS, Rosenzweig KE et al: Improved Outcomes with Modern Lung-Sparing Trimodality Therapy in Patients with Malignant Pleural Mesothelioma. J Thorac Oncol 2017, 12(6):993-1000. 5. Allen AM, Czerminska M, Janne PA, Sugarbaker DJ, Bueno R, Harris JR, Court L, Baldini EH: Fatal pneumonitis associated with intensity-modulated radiation therapy for mesothelioma. Int J Radiat Oncol Biol Phys 2006, 65(3):640-645. 6. Chan MF, Chui CS, Song Y, Burman C, Yorke E, Della-Biancia C, Rosenzweig KE, Schupak K: A novel radiation therapy technique for malignant pleural mesothelioma combining electrons with intensity-modulated photons. Radiother Oncol 2006, 79(2):218-223. 7. Sterzing F, Sroka-Perez G, Schubert K, Munter MW, Thieke C, Huber P, Debus J, Herfarth KK: Evaluating target coverage and normal tissue sparing in the adjuvant radiotherapy of malignant pleural mesothelioma: helical tomotherapy compared with step-and-shoot IMRT. Radiother Oncol 2008, 86(2):251-257. 8. Scorsetti M, Bignardi M, Clivio A, Cozzi L, Fogliata A, Lattuada P, Mancosu P, Navarria P, Nicolini G, Urso G et al: Volumetric modulation arc radiotherapy compared with static gantry intensity-modulated radiotherapy for malignant pleural mesothelioma tumor: a feasibility study. Int J Radiat Oncol Biol Phys 2010, 77(3):942-949. 9. Krayenbuehl J, Hartmann M, Lomax AJ, Kloeck S, Hug EB, Ciernik IF: Proton therapy for malignant pleural mesothelioma after extrapleural pleuropneumonectomy. Int J Radiat Oncol Biol Phys 2010, 78(2):628-634. 10. de Perrot M, Feld R, Leighl NB, Hope A, Waddell TK, Keshavjee S, Cho BC: Accelerated hemithoracic radiation followed by extrapleural pneumonectomy for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2016, 151(2):468-473. 11. Davis SR, Tan L, Ball DL: Radiotherapy in the treatment of malignant mesothelioma of the pleura, with special reference to its use in palliation. Australas Radiol 1994, 38(3):212-214.

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