Phase II trial of neoadjuvant pemetrexed plus cisplatin followed by surgery and radiation in the treatment of pleural mesothelioma

Our plain-English summary of Phase II trial of neoadjuvant pemetrexed plus cisplatin followed by surgery and radiation in the treatment of pleural mesothelioma, by R. Federico, F. Adolfo, M. Giuseppe, et al (BMC Cancer, 2013).

The study

• Authors: R. Federico, F. Adolfo, M. Giuseppe, S. Lorenzo, D.T. Martino, C. Anna, P. Adriano, C. Gino, R. Francesca, C. Matteo, K. Gbenga, M. Paolo, F. Francesco
• Journal: BMC Cancer
• Published: 2013;13:22
• Cited by: 47 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma is an aggressive tumor that has a poor prognosis and is resistant to unimodal approaches. Multimodal treatment has provided encouraging results.

Methods: Phase II, open-label study of the combination of chemotherapy (pemetrexed 500 mg/m²+cisplatin 75 mg/m² IV every 21 days × 3 cycles), followed by surgery (en-bloc extrapleural pneumonectomy, 3-8 weeks after chemotherapy) and hemithoracic radiation (total radiation beam 54 Gy, received 4-8 weeks post-surgery). The primary endpoint was event-free survival, defined as the time from enrollment to time of first observation of disease progression, death due to any cause, or early treatment discontinuation.

Results: Fifty-four treatment-naïve patients with T1-3 N0-2 malignant pleural mesothelioma were enrolled, 52 (96.3%) completed chemotherapy, 45 (83.3%) underwent surgery, 22 (40.7%) completed the whole treatment including 90-day post-radiation follow-up. The median event-free survival was 6.9 months (95%CI: 5.0-10.5), median overall survival was 15.5 months (95%CI 11.0-NA) while median time-to-tumor response was 4.8 months (95%CI: 2.5-8.0). Eighteen (33.3%) and 13 (24.1%) patients were still event-free after 1 and 2 years, respectively. The most common treatment-emergent adverse events were nausea (63.0%), anemia (51.9%) and hypertension (42.6%).Following two cardiopulmonary radiation-related deaths the protocol was amended (21 [38.9%] patients were already enrolled in the study): the total radiation beam was reduced from 54 Gy to 50.4 Gy and a more accurate selection of patients was recommended.

Conclusions: The combination of pemetrexed plus cisplatin followed by surgery and hemithoracic radiation is feasible and has a manageable toxicity profile in carefully selected patients. It may be worthy of further investigation.

Trial Registration: Clinicaltrial.com registrationID #NCT00087698.

In plain English

This phase II, open-label, non-randomized trial ran at four centers in Italy from June 2005 to February 2010. It tested three treatments in sequence for malignant pleural mesothelioma: pemetrexed plus cisplatin chemotherapy, then extrapleural pneumonectomy surgery, then radiation to one side of the chest. It did not study asbestos exposure. Of 54 previously untreated patients with stage I to III disease, 52 completed chemotherapy, 45 had surgery and 22 (40.7%) completed the whole treatment including 90-day post-radiation follow-up. Measured from enrollment, median event-free survival was 6.9 months (95% CI 5.0 to 10.5) and median overall survival was 15.5 months (95% CI 11.0 to not assessable). Eleven patients died during the study, two from study drug toxicity (cardiopulmonary failures) and four from procedures. After two cardiopulmonary deaths, the radiation dose was cut from 54 Gy to 50.4 Gy and patient selection was tightened. Outcomes looked better afterwards, but the authors made no claim of statistical significance. The authors concluded the approach is feasible, with manageable toxicity, in carefully selected patients.

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: Phase II, open-label, non-randomized multicenter clinical trial of trimodality treatment (chemotherapy, surgery, radiation)
• Who was studied: 54 treatment-naïve patients with clinical stage I to III (T1-3 N0-2) malignant pleural mesothelioma, enrolled out of 56 screened at four centers in Italy from June 2005 to February 2010; 47 (87%) were men, median age 63.0 years
• Exposure: No asbestos exposure was studied. The intervention was pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 every 21 days for 3 cycles, then extrapleural pneumonectomy 3 to 8 weeks later, then hemithoracic radiation (54 Gy, reduced to 50.4 Gy after a protocol amendment)
• Main results:
  • Of 54 enrolled patients, 52 (96.3%) completed chemotherapy, 45 (83.3%) underwent surgery and 22 (40.7%) completed the whole treatment including 90-day post-radiation follow-up
  • All enrolled patients, measured from enrollment: median event-free survival was 6.9 months (95% CI 5.0 to 10.5); 18 (33.3%) and 13 (24.1%) patients were event-free at 1 and 2 years
  • All enrolled patients, measured from enrollment: median overall survival was 15.5 months (95% CI 11.0 to not assessable); the 1-year overall survival rate was 59.2% (95% CI 44.9 to 70.9)
  • All enrolled patients: median progression-free survival was 8.6 months (95% CI 6.3 to 14.4)
  • 11 patients died during the study: two deaths were due to study drug toxicity (cardiopulmonary failures), four were procedure related and five were considered unrelated. Two of the 45 surgical patients (4.4%) died within 30 days of surgery
  • The most common treatment-emergent adverse events were nausea (63.0%), anemia (51.9%) and hypertension (42.6%); 36 patients (66.7%) had at least one grade 3/4 toxicity
  • After two cardiopulmonary deaths, the protocol was amended: total radiation was reduced from 54 Gy to 50.4 Gy and patient selection was made stricter. 21 patients (38.9%) had been enrolled before the amendment
  • Median event-free survival was 6.3 months in patients enrolled before the amendment and 8.1 months in those enrolled after. The authors stated that no claim of statistical significance could be made for before-versus-after differences. They suggested the lower radiation dose might improve outcomes and said this hypothesis needs confirmation
• The authors' conclusion: The authors concluded that pemetrexed plus cisplatin followed by surgery and hemithoracic radiation is feasible and has a manageable toxicity profile in carefully selected patients, and may be worthy of further investigation
• Limitations the authors state:
  • The sample size was not recalculated after the protocol amendment, so comparisons before and after the amendment were not powered and analyses were limited to overall outcomes
  • After the amendment, patients were not enrolled equally across all study centers, a possible source of bias
  • The low completion rate (40.7%) points to the need for careful patient selection

Topics

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

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

Related studies

• Trimodality strategy for treating malignant pleural mesothelioma: results of a feasibility study of induction pemetrexed plus cisplatin followed by extrapleural pneumonectomy and postoperative hemithoracic radiation (Japan Mesothelioma Interest Group 0601 Trial) — S. Hasegawa, M. Okada, et al. (2016)
• Complete pathological response to neoadjuvant pemetrexed/cisplatin in combination with regional hyperthermia in a patient with sarcomatoid peritoneal mesothelioma — S. Kruger, M.K. Angele, et al. (2014)
• Importance of excision repair cross-complementation group 1 and ribonucleotide reductase M1 as prognostic biomarkers in malignant pleural mesothelioma treated with platinum-based induction chemotherapy followed by surgery — L. Frischknecht, M. Meerang, et al. (2015)
• A feasibility study of induction pemetrexed plus cisplatin followed by pleurectomy/decortication aimed at macroscopic complete resection for malignant pleural mesothelioma — M. Shimokawa, S. Hasegawa, et al. (2013)
• Comparison of cisplatin plus pemetrexed and cisplatin plus gemcitabine for the treatment of malignant pleural mesothelioma in Japanese patients — T. Shukuya, T. Takahashi, et al. (2014)
• 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)

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