Radiotherapy Confers No Additional Benefit for Mesothelioma

Fran Lowry

November 11, 2015

Nonrandomized studies have suggested that radiotherapy, given after surgery and chemotherapy, affords an extra survival benefit in patients with malignant pleural mesothelioma.

Now, a multicenter randomized phase 2 trial has shown that radiotherapy has no benefit, and might actually cause harm.

In the SAKK 17/04 trial, patients with malignant pleural mesothelioma who had been treated with neoadjuvant chemotherapy and extrapleural pneumonectomy were randomized to receive high-dose radiotherapy or no radiotherapy.

Median overall survival was shorter in the radiotherapy group than in the no-radiotherapy group (19 vs 21 months).

"Our findings do not support the routine use of hemithoracic radiotherapy for malignant pleural mesothelioma after neoadjuvant chemotherapy and extrapleural pneumonectomy," write Rolf A. Stahel, MD, from the University Hospital of Zurich, and his fellow trialists in their study, published online November 2 in the Lancet Oncology.

The team calls their trial "sobering," and adds that current concepts for the treatment of malignant pleural mesothelioma need to be revised.

Dr Tom Treasure

"We welcome the findings of the SAKK 17/04 trial," write Robert C. Rintoul, MD, from the Papworth Hospital in Cambridge, Tom Treasure, MD, from University College, and Fergus Macbeth, MD, from the University of Cardiff, all in the United Kingdom, in their accompanying comment.

"The heterogeneity of mesothelioma and the multiplicity of treatments make it impossible to separate the signal from the noise without control groups," they explain.

"More randomized trials are needed so that even if the lives of patients with mesothelioma cannot be extended, at least they will not be given treatments that make their lives worse," they add.

The investigators developed their phase 2 trial on the basis of evidence from three studies: a previous study of neoadjuvant chemotherapy and extrapleural pneumonectomy, in which median survival was 23 months; the SAKK 17/04 feasibility study of neoadjuvant chemotherapy and extrapleural pneumonectomy for malignant pleural mesothelioma; and a single-center report on the reduction in local relapses with hemithoracic radiation in patients with mesothelioma after extrapleural pneumonectomy.

The SAKK 17/04 trial was conducted in two parts at 12 hospitals in Switzerland, one hospital in Belgium, and one hospital in Germany.

All patients had histologically confirmed malignant pleural mesothelioma, were considered to be completely resectable on the basis of CT, PET and CT, and in some cases MRI, and were assessed by a thoracic oncology tumor board, which included a thoracic surgeon.

Additionally, all had a WHO performance status of 0 or 1, and were 18 to 70 years of age.

In part 1 of the study, 113 patients received three cycles of neoadjuvant chemotherapy (cisplatin 75 mg/m² and pemetrexed 500 mg/m² on day 1 given every 3 weeks) and extrapleural pneumonectomy.

In part 2, half the 54 patients who achieved complete macroscopic resection were randomly assigned to high-dose hemithoracic radiotherapy and half were assigned to no radiotherapy. Twenty-five of the 27 patients completed radiotherapy.

The median total dose of radiotherapy was 55.9 Gy (interquartile range, 46.8 - 56.0).

The most common toxic effects of grade 3 or higher in the radiotherapy group were nausea or vomiting, esophagitis, and pneumonitis, which was fatal in one patient.

Table. Adverse Reactions to Radiotherapy

Toxic Effect Grade 1/2, % Grade 3, % Grade 4, % Grade 5, %
Anemia 74 0 0 0
Nausea or vomiting 30 11 0 0
Fatigue 22 4 0 0
Anorexia 26 0 0 0
Esophagitis 22 7 0 0
Radiation dermatitis 22 0 0 0
Thrombocytopenia 19 0 0 0
Weight loss 15 0 0 0
Leucopenia 15 0 0 0
Increased creatinine concentration 15 0 0 0
Pneumonitis 0 0 4 4
Dyspnea 0 4 0 0
Diarrhea 0 4 0 0
Increased alkaline phosphatase concentration 0 4 0 0


Median relapse-free survival after randomization was 7.6 months (95% confidence interval [CI], 5.2 - 10.6) in the radiotherapy group and 5.7 months (95% CI, 3.5 - 8.8) in the no-radiotherapy group.

Median locoregional relapse-free survival after surgery was 9.4 months (95% CI, 6.5 - 11.9) in the radiotherapy group and 7.6 months (95% CI, 4.5 - 10.7) in the no-radiotherapy group.

Median overall survival from the time of enrollment in part 2 of the study was 19.3 months (95% CI, 11.5 - 21.8) in the radiotherapy group and 20.8 months (95% CI, 14.4 - 27.8) in the no-radiotherapy group.

"The overall median survival of 20 months in part 2 was less than expected when compared with — often retrospective — clinical reports," Dr Stahel and colleagues write. "According to the results of our trial, hemithoracic radiotherapy after extrapleural pneumonectomy resulting in a macroscopically complete resection provides an additional treatment burden without benefiting the patient."

Unwarranted Enthusiasm From Observational Studies

"Yet again, a randomized study has shown that data from observational studies might engender unwarranted enthusiasm. The same was seen in the MARS study (concerning extrapleural pneumonectomy) and the MesoVATS study (concerning video-assisted thoracoscopic pleurectomy)," Dr Rintoul and his colleagues write in their comment.

People make wrong guesses.

"Randomized trials of multimodality cancer treatments are difficult to do but not impossible, as the SAKK trialists have shown," Dr Treasure, who was the principal investigator for the MARS trial, told Medscape Medical News.

"Without the discipline of a controlled trial, we can only guess which component provides benefit and which only does harm, and people make wrong guesses," he explained.

This study was sponsored by Swiss Group for Clinical Cancer Research (SAKK); the Swiss State Secretariat for Education, Research, and Innovation; and Eli Lilly. The study authors and Dr Rintoul, Dr Treasure, and Dr Macbeth have disclosed no relevant financial relationships.

Lancet Oncol. Published online November 2, 2015. Abstract, Comment


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