Trimodality therapy for malignant pleural mesothelioma: results from an EORTC phase II multicentre trial

Our plain-English summary of Trimodality therapy for malignant pleural mesothelioma: results from an EORTC phase II multicentre trial, by P.E. Van Schil, P. Baas, R. Gaafar, et al (The European Respiratory Journal, 2010).

The study

• Authors: P.E. Van Schil, P. Baas, R. Gaafar, A.P. Maat, M. Van de Pol, B. Hasan, H.M. Klomp, A.M. Abdelrahman, J. Welch, J.P. van Meerbeeck, European Organisation for Research and Treatment of Cancer (EORTC) Lung Cancer Group
• Journal: The European Respiratory Journal
• Published: 2010;36(6):1362-9
• Cited by: 180 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The European Organisation for Research and Treatment of Cancer (EORTC; protocol 08031) phase II trial investigated the feasibility of trimodality therapy consisting of induction chemotherapy followed by extrapleural pneumonectomy and post-operative radiotherapy in patients with malignant pleural mesothelioma (with a severity of cT3N1M0 or less). Induction chemotherapy consisted of three courses of cisplatin 75 mg·m⁻² and pemetrexed 500 mg·m⁻². Nonprogressing patients underwent extrapleural pneumonectomy followed by post-operative radiotherapy (54 Gy, 30 fractions). Our primary end-point was "success of treatment" and our secondary end-points were toxicity, and overall and progression-free survival. 59 patients were registered, one of whom was ineligible. Subjects' median age was 57 yrs. The subjects' TNM scores were as follows: cT1, T2 and T3, 36, 16 and six patients, respectively; cN0 and N1, 57 and one patient, respectively. 55 (93%) patients received three cycles of chemotherapy with only mild toxicity. 46 (79%) patients received surgery and 42 (74%) had extrapleural pneumonectomy with a 90-day mortality of 6.5%. Post-operative radiotherapy was completed in 37 (65%) patients. Grade 3-4 toxicity persisted after 90 days in three (5.3%) patients. Median overall survival time was 18.4 months (95% CI 15.6-32.9) and median progression-free survival was 13.9 months (95% CI 10.9-17.2). Only 24 (42%) patients met the definition of success (one-sided 90% CI 0.36-1.00). Although feasible, trimodality therapy in patients with mesothelioma was not completed within the strictly defined timelines of this protocol and adjustments are necessary.

In plain English

This phase II trial (European Organisation for Research and Treatment of Cancer protocol 08031), run at 11 centres from July 2005 to August 2007, tested whether three-part ("trimodality") treatment was feasible in limited malignant pleural mesothelioma. Treatment was three cycles of cisplatin and pemetrexed, then extrapleural pneumonectomy (removing the lung, pleura, diaphragm and pericardium), then 54 Gy of radiotherapy. Of 59 registered patients, one was ineligible; known asbestos exposure was recorded in 44 of 58 eligible patients (75.9%). Fifty-five received three chemotherapy cycles, 46 had surgery, 42 had pneumonectomy and 37 completed radiotherapy. Mortality at 30 and 90 days was 6.5% (three of 46 surgical patients). Only 24 of 57 eligible patients who started treatment (42.1%; one-sided 90% CI 0.36 to 1.00) met the predefined "success" definition, so the primary end-point was not reached. Median overall survival in those 57 was 18.4 months (95% CI 15.6 to 32.9); median progression-free survival was 13.9 months (95% CI 10.9 to 17.2). The authors concluded it seemed feasible in selected patients but did not warrant use outside expert institutions, preferably within clinical trials.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Prospective phase II multicentre feasibility trial (EORTC protocol 08031) of trimodality treatment
• Who was studied: 59 patients were registered from 11 centres (in Belgium, the Netherlands, Egypt, Italy, France and the UK) between July 2005 and August 2007. All had pathologically proven malignant pleural mesothelioma of stage cT3N1M0 or less. One patient was ineligible. The 58 eligible patients were 46 male and 12 female, with a median age of 57 years (range 26 to 67).
• Exposure: The study examined a treatment, not asbestos exposure. Known asbestos exposure was reported in 44 (75.9%) of the 58 eligible patients. The treatment was three cycles of pemetrexed 500 mg per square metre with cisplatin 75 mg per square metre, then extrapleural pneumonectomy, then post-operative radiotherapy of 54 Gy.
• Main results:
  • Three cycles of chemotherapy were given to 55 (94.8%) patients; three (5.2%) patients received two cycles.
  • Of the 58 eligible patients, 46 (79.3%) had surgery.
  • Extrapleural pneumonectomy was performed in 42 patients. This was 91.3% of the 46 who had surgery and 73.7% of eligible patients who started treatment.
  • Among the 46 surgical patients, mortality at 30 and 90 days was 6.5%. The trial diagram records three post-operative deaths. The causes were pulmonary embolism, combined lung oedema and pneumonia, and progressive disease.
  • Post-operative radiotherapy was started in 38 patients and completed in 37 (63.8% of all eligible patients).
  • Only 24 (42.1%) of the 57 eligible patients who started treatment met the primary end-point definition of success. Success meant receiving full protocol treatment within the time-frames, and being alive 90 days afterwards without progression or grade 3 to 4 toxicity. The one-sided 90% CI was 0.36 to 1.00.
  • In a sensitivity analysis that relaxed only the treatment timelines, the number of successes among the 57 patients rose to 28 (one-sided 90% CI 0.399 to 1.00). The authors described this as borderline for declaring the study a success.
  • For all 57 eligible patients who started treatment, median overall survival was 18.4 months (95% CI 15.6 to 32.9). The 1-year survival rate was 70.2% (95% CI 56.5 to 80.3).
  • For the same 57 patients, median progression-free survival was 13.9 months (95% CI 10.9 to 17.2).
  • Grade 3 to 4 toxicity persisted 90 days after the end of treatment in three (5.7%) patients. The causes were bronchopleural fistula (two patients) and grade 3 radiation pneumonitis (one patient).
  • For the 37 patients who completed trimodality treatment, median overall survival was 33 months. The authors noted that this median was hardly reached.
• The authors' conclusion: The authors concluded that trimodality treatment seems feasible in selected patients with early stage mesothelioma. However, they found that the results do not warrant its use outside selected institutions with high levels of expertise, and preferably only within prospective clinical trials.
• Limitations the authors state:
  • The authors stated that, looking back, the predefined success criteria might be considered unrealistic.
  • The authors stated that the median survival among patients who completed treatment was hardly reached, and that longer follow-up is needed.
  • The authors noted that overall treatment time is long.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Trimodality Therapy, Pleural Mesothelioma, Chemotherapy, Extrapleural Pneumonectomy (EPP), Cisplatin, Pemetrexed (Alimta), Progression-Free Survival, Median Overall Survival.

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• Survival after trimodality therapy for malignant pleural mesothelioma: Radical Pleurectomy, chemotherapy with Cisplatin/Pemetrexed and radiotherapy — S. Bölükbas, C. Manegold, et al. (2011)
• Tumour Treating Fields in combination with pemetrexed and cisplatin or carboplatin as first-line treatment for unresectable malignant pleural mesothelioma (STELLAR): a multicentre, single-arm phase 2 trial — G.L. Ceresoli, J.G. Aerts, et al. (2019)
• Phase I trial of cisplatin, pemetrexed, and imatinib mesylate in chemonaive patients with unresectable malignant pleural mesothelioma — A.S. Tsao, N. Harun, et al. (2014)
• Durvalumab with first-line chemotherapy in previously untreated malignant pleural mesothelioma (DREAM): a multicentre, single-arm, phase 2 trial with a safety run-in — A.K. Nowak, W.J. Lesterhuis, et al. (2020)
• Prophylactic radiotherapy for the prevention of procedure-tract metastases after surgical and large-bore pleural procedures in malignant pleural mesothelioma (SMART): a multicentre, open-label, phase 3, randomised controlled trial — A.O. Clive, H. Taylor, et al. (2016)

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