A Feasibility Study Evaluating Surgery for Mesothelioma After Radiation Therapy Using Extensive Pleural Resection (SMARTER)

This study aims to find the maximum tolerated dose level for malignant pleural mesothelioma patients receiving background radiation + boost radiation, and surgery. Boost radiation is an experimental form of radiation that involves targeting non-uniform high doses of radiation to bulky pleural masses. We hypothesize the immunologic abscopal effect is an important component in controlling disease, and may be stimulated with highly hypofractionated doses. Doses will increase with every three patients who will be enrolled in the study until the background radiation reaches 1800 cGy or the maximum tolerated dose, whichever is lower.

Study Overview

• Status: Active, not recruiting
• Conditions: Mesothelioma; Lung
• Intervention / Treatment: Radiation: Varying Doses of Background and Boost RT

Detailed Description

This study aims to find the maximum tolerated dose level for mesothelioma patients receiving background radiation + boost radiation, and surgery. 3 patients will start with a background radiation therapy (RT) dose of 0 cGy, and boost RT of at least 2100 cGy. If the radiation is manageable (radiation related AEs grade < 4), the next set of 3 patients will be enrolled, and the background radiation dose will be increased by 600 cGy. This will continue until the background radiation dose reaches 1800 cGy. If 1 patient exhibits dose limiting toxicities (AEs grade 4 & 5), the dose level will repeat with the next 3 patients. If 2 or more patients exhibit DLTs, the previous dose level will be determined as the maximum tolerated dose level. Surgery will be scheduled to occur approximately 1-2 weeks after completing radiation therapy, and will subsequently be followed up as per study schedule.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Hospital, University Health Network

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Good pulmonary function precluding radiation therapy (FEV1>1 L or >40% predicted or DLCO >45% predicted)
• Any patient with a new histological diagnosis of malignant pleural mesothelioma (MPM). Sarcomatoid or biphasic histologies can be included but will be analyzed separately due to their poor prognosis.
• Stage T1-3 N0-1 M0 according to the 8th edition of the tumor, node, and metastases (TNM) staging system based on conventional investigations and tests (Appendix 1). Note that the updated TNM staging system now categorizes ipsilateral mediastinal nodes as N1 disease.
• Suitable for combined modality therapy
• Informed consent.

Exclusion Criteria:

• Age < 18 years.
• Contralateral mediastinal nodal disease (N2)
• Distant metastatic disease (M1).
• Poor performance status ECOG 3-4.
• Poor pulmonary function precluding radiation therapy (FEV1<1 L or <40% predicted or diffusion lung capacity for carbon monoxide (DLCO) <45% predicted)
• Failure to provide informed consent.
• Previous thoracic irradiation.
• Serious non-malignant disease (e.g. cardiovascular, pulmonary, systemic lupus erythematosus (SLE), scleroderma) which would preclude definitive radiation treatment.
• Previous chemotherapy for this or concurrent malignancy.
• Previous or concomitant malignancies except for patients with non-melanoma skin cancer, contralateral non-invasive breast cancer, prostate cancer treated with curative intent or carcinoma in situ of any other site. In addition, patients with invasive cancers treated more than 3 years previously and without evidence of recurrence will be eligible.
• Women who are currently pregnant or lactating.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Radiation; This study involves a 3+3 design. The starting cohort (n=3) will receive a neoadjuvant Background dose to the affected hemithorax (starting at 0 cGy) as well as concomitant Boost dose (of at least 2100 cGy) to a part of the gross tumour volume (GTV). The radiation will be delivered over 3 alternate days over 5-7 calendar days followed by macroscopically complete extensive pleural resection (either extra-pleural pneumonectomy or extended pleurectomy decortication, at the surgeon's discretion) after 7 to 14 days. If no dose limiting toxicities (DLTs) seen, then the Background RT dose will be increased by 600 cGy (up to 1800 cGy) and the cohort (n=3) for the next dose level will be accrued. If only 1 DLT seen, then an additional 3 patients will be treated on this dose level. If 2 or more DLTs seen at any given dose level, then the previous dose level will be defined as the maximum tolerated dose (MTD). Patients will be stratified by type of resection.

Radiation: Varying Doses of Background and Boost RT; 3+3 radiation dose escalation model to see the maximum tolerated dose for background and boost radiation therapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose for Background Radiation	AEs will be graded by CTCAE. Maximum tolerated dose is the dose level that do not result in fatal lung injury (grade 5 lung toxicity) or life-threatening or fatal treatment related toxicity (grade 4+).	Up to five years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient Morbidity	NCI common toxicity scale	Up to five years
Local recurrence	Documented radiographically	Up to five years
Patients' quality of life	Short Form Health Survey-36 (SF-36) Form	Up to five years
Evaluating patients' pain	Assess by using the Short Form (BPI-SF)	Up to five years
Evaluating patients' pain	Assess by using The Hospital Anxiety and Depression Scale (HADS)	Up to five years
Evaluating patients' pain	Assess by using the EuroQol EQ-5D-5L Questionnaire	Up to five years
Evaluating patients' pain	Assess by using the Sensitivity to Pain Traumatization Scale (SPTS)	Up to five years
Evaluating patients' pain	Assess by using the ID Pain form	Up to five years
Evaluating patients' pain	Assess by using the Pain Catastrophizing Scale (PCS)	Up to five years
Evaluating patients' pain	Assess by using the Post-traumatic Stress Disorder Checklist-Civilian version (PCL-C)	Up to five years
Evaluating patients' pain	Assess by using a variety of standard instruments including the Injustice Experience Questionnaire (IEQ).	Up to five years

Collaborators and Investigators

• Sponsor: University Health Network, Toronto
• Investigators: Principal Investigator: John Cho, MD, PhD, Princess Margaret Hospital, Canada

Study record dates

Study Major Dates

• Study Start (Actual): September 5, 2019
• Primary Completion (Estimated): April 1, 2024
• Study Completion (Estimated): April 1, 2025

Study Registration Dates

• First Submitted: April 3, 2019
• First Submitted That Met QC Criteria: July 18, 2019
• First Posted (Actual): July 22, 2019

Study Record Updates

• Last Update Posted (Actual): October 27, 2023
• Last Update Submitted That Met QC Criteria: October 25, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Surgery; Radiation; Boost Radiation Therapy; Background Radiation Therapy; Extensive Pleural Resection
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Adenoma; Neoplasms, Mesothelial; Pleural Neoplasms; Mesothelioma; Mesothelioma, Malignant
• Other Study ID Numbers: 18-5987

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No