A preoperative accelerated high-dose radiation therapy protocol for advanced mesothelioma has led to a 3-year survival more than twice what would have been expected with more conventional strategies, a small clinical study showed.
The 25 evaluable patients have a projected 3-year survival of 72% with the 1-week SMART (Surgery for Mesothelioma After Radiation Therapy) protocol, as compared with an expected 3-year survival of 32% with other treatment strategies.
No patient developed grade 3 to 5 toxicity associated with the radiation therapy, as reported online in the Journal of Thoracic Oncology.
"The therapeutic indication for SMART differs from standard induction protocols of radiation and chemoradiation since the short time course of radiation does not allow meaningful cytoreductive downstaging," Marc de Perrot, MD, of Princess Margaret Cancer Center in Toronto, and colleagues concluded.
"SMART aims to induce a tumorostatic and tumoricidal effect to prevent or delay the successful implantation of clonogens to distant sites at time of the extrapleural pneumonectomy [EPP]."
A direct consequence of exposure to asbestos, the incidence of mesothelioma is expected to plateau by the end of the decade in most industrialized nations, more than 30 years after the nations banned the use of asbestos. Many developing countries do not regulate use of asbestos, however, which could lead to another upswing in the incidence of malignant pleural mesothelioma, the authors noted.
Although median survival for patients with mesothelioma is less than a year, EPP offers the best chance for prolonged survival. Optimal treatment for patients with resectable mesothelioma remains controversial, they continued.
Neoadjuvant chemotherapy, followed by EPP and adjuvant radiation therapy has led to a 3-year survival of 53% and median survival of almost 5 years for patients without locally advanced or metastatic disease at the authors' center. However, the strategy leaves patients susceptible to distant metastasis.
Distant metastasis could reflect inadvertent release of microscopic disease during surgery, de Perrot and colleagues said. If true, neoadjuvant treatment to achieve tumoricidal or tumorostatic effects might prevent distant spread. This hypothesis led to development of the SMART protocol and a phase I/II clinical trial.
The investigators enrolled patients with previously untreated T1-3N0M0 mesothelioma that was amenable to EPP. Preoperative intensity-modulated radiation therapy (IMRT) consisted of a 25-Gy dose administered in five daily fractions, plus a 5-Gy boost to the tumor and tract sites. All patients underwent EPP within a week after completing neoadjuvant radiation therapy.
Patients with evidence of mediastinal lymph node involvement were eligible for adjuvant chemotherapy.
All but one patient had T3-4 disease, and 14 patients had nodal involvement (N2 in 12 of 14).
All 25 patients completed the SMART protocol with no operative deaths. EPP was performed an average of 6 days after completion of IMRT. One patient developed empyema and died 88 days after surgery.
All of the patients had stage III or IV on final pathology, and five of 13 patients with nodal involvement received adjuvant chemotherapy.
After a median follow-up of 23 months, the 3-year survival was 84% in the 16 patients with epithelial subtype disease versus 13% in nine patients with biphasic subtype mesothelioma.
His team has treated an additional 20 patients who were not included in their report, and 3-year overall survival is approaching 90%, according to de Perrot.
The results are encouraging and deserve further study, but the trial has several limitations, said Jae Kim, MD, of City of Hope in Duarte, Calif.
"It's difficult to draw definitive conclusions due to the lack of a comparison group, the relatively small number of patients in the study, and the short follow-up," Kim said by email. "One important question is whether this type of therapy can be incorporated into a lung-sparing approach.
"At our institution, we try to preserve the lung by performing radical pleurectomy whenever possible rather than extrapleural pneumonectomy. In this approach, all visible tumor is removed, but the lung is left in place. This has been shown to offer similar survival as extrapleural pneumonectomy but with better quality of life."
Data reported last year at the American Society of Radiation Oncology meeting suggested that radiation therapy can be administered safely after radical pleurectomy, Kim added.
The study was supported by the Princess Margaret Hospital Foundation Mesothelioma Research Fund.
The authors reported no relevant disclosures.
- Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner