Mesothelioma Treatment in Toronto Moves from SMART to SMARTER

The Princess Margaret Cancer Center in Toronto has moved from SMART to SMARTER with the recent launch of its latest clinical trial for pleural mesothelioma patients.

SMARTER is the acronym for Surgery for Mesothelioma After Radiation Therapy using Extensive pleural Resection, which also describes the latest clinical trial.

The phase I clinical trial is an unconventional approach to treatment of mesothelioma: Find the maximum tolerated dosage of hypofractionated radiation to stimulate the immune system before aggressive surgery.

It comes on the heels of the SMART protocol, which stands for Surgery for Mesothelioma After Radiation Therapy. It involved higher doses of radiation that required an more aggressive surgery.

“The genesis for this latest trial is based on what we learned from the first version, the SMART version, and in terms of extending disease free outcomes, we were very pleased,” Dr. John Cho, radiation oncologist and principal trial investigator, told The Mesothelioma Center at Asbestos.com. “Now we’ve gone back to the drawing board, looking for similar results but with a much less aggressive procedure.”

Impressive Earlier Survival Times

The research team in Toronto reported a three-year survival rate of 66% among patients with the epithelial mesothelioma subtype and no lymph node involvement while using the SMART approach.

They also estimated a median overall survival of 51 months and disease-free survival at 47 months.

The high-dose radiation administered in the SMART trial was used only with the radical extrapleural pneumonectomy (EPP) surgery, which removes the entire lung, eliminating the option of the less aggressive lung-sparing pleurectomy/decortication (P/D) surgery.

In the United States, most multimodal mesothelioma treatment starts with chemotherapy before aggressive surgery and ends with radiation if used at all. Most centers have moved away from using the EPP surgery.

“In the SMART trial, one of the issues was that the recovery was very challenging, usually 3-6 months. Some patients are too frail and unable to handle the big operation,” Cho said. “With SMARTER, the surgery is less aggressive, and patients can bounce back better. And a lot of surgeons today are not comfortable with the EPP.”

Finding the Radiation ‘Sweet Spot’

Researchers in Toronto still believe that the use of high-dose hypofractionated radiation makes surgery more effective by stimulating the immune system. Patients will receive radiation three times over a seven-day period in the trial.

Because the radiation dosage level will be lower than in the SMART trial, surgeons will have the option of using the less-aggressive P/D surgery. The goal will be finding the highest possible dosage level without damaging lung tissue that require the EPP.

“The idea is to tweak the radiation dosage in the optimal way to enhance the immune system,” Cho said. “At some point, radiation can have a negative effect on the immune system. It’s about finding the ideal dose, the sweet spot, where it does the most good.”

Once the ideal radiation dosage level is found, the clinical trial will add an immunotherapy drug and move into the SMARTEST phase, otherwise known as Surgery for Mesothelioma After Radiation Therapy using Extensive Systemic Therapy.

“Our belief is that patients do better if we can optimize all the components of treatment,” Cho said. “The immune system is complicated, but it can have a dramatic effect. Radiation can be part of that.”

Traditional radiation is given mostly in a palliative setting with mesothelioma, although previous studies with lung cancer have shown that high doses can increase the effectiveness of certain immunotherapy drugs.

Who Is Eligible for the Clinical Trial?

Any patient with a new histological diagnosis of pleural mesothelioma is eligible for this clinical trial, including those with sarcomatoid and biphasic subtypes, which are the toughest ones to treat. Previous chemotherapy for mesothelioma would make patients ineligible for the trial.

Cho has been working closely with thoracic surgeon and mesothelioma specialist Dr. Marc de Perrot at Toronto General Hospital.

Perrot recently wrote an editorial in 2018 for the Journal of Thoracic Disease, suggesting that the radiation/immunotherapy/surgery combination could become standard of care for pleural mesothelioma patients.

“We would like less toxicity and better outcomes. That would be our hope,” Cho said. “This is exciting, but at the same time, we don’t want to get ahead of ourselves. We want to manage expectations. We’re not actually curing patients. We’re pushing disease progression down the road.”

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