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Interim Analysis of a Phase 2 Toxicity Study on Hemithoracic Pleural Intensity Modulated Radiation Therapy (IMRT) for Malignant Pleural Mesothelioma (MPM)

      Purpose/Objective(s)

      Adjuvant radiation therapy for MPM is particularly challenging after pleurectomy/decortication (P/D) due to the presence of two intact lungs at risk for radiation pneumonitis (RP). We recently reported our initial experience with hemithoracic pleural IMRT in 36 MPM patients with two intact lungs. Based on the promising results, a phase II study was launched to prospectively characterize the safety of IMRT to the pleura as part of a multimodality treatment approach. Here, we present an interim analysis of the primary toxicity endpoint of the study.

      Materials/Methods

      All patients with newly diagnosed locally advanced MPM received up to 4 cycles of pemetrexed/platinum chemotherapy. If feasible, P/D was performed. Hemithoracic pleural IMRT was then administered in 28 fractions for a total planned dose of 50.4 Gy, as previously described. A Simon two-stage design was used with a safety analysis after the first 9 patients. As only one case developed grade ≥3 RP over 3 months, the cohort was expanded to 28 evaluable patients, defined as having initiated RT. The primary endpoint was the incidence of grade ≥3 RP defined per Common Terminology Criteria for Adverse Events, v4.0. Steroids were initiated for grade ≥2 RP.

      Results

      To date, 19 evaluable patients out of 27 patients total have been enrolled with a median follow-up of 10 months. The median age was 65 (range, 38-79). Median KPS was 90% (range, 70-90%). Five patients had sarcomatoid or biphasic and 22 had epithelioid MPM. Of those who underwent surgical exploration, 86% had pathologic stage III or IV MPM. Four patients underwent an extended P/D, 9 had a partial P/D, and 14 were unresectable. Six patients came off-study prior to receiving IMRT (5 due to disease progression and 1 due to grade 4 pulmonary embolism after one cycle of chemotherapy). Eighteen patients have completed IMRT [median dose 4680 cGy (range, 4500 to 5040 cGy)]; one patient had distant disease progression after 16 fractions; 2 patients are currently completing their chemotherapy. Four patients experienced grade 2 RP with symptom improvement after steroid initiation. Only one patient experienced grade 3 RP and was weaned from oxygen shortly after a course of steroids. Other grade ≥2 radiation-related toxicities included fatigue (42%), dyspnea (47%), nausea (42%), esophagitis (32%), and cough (11%). No grade 4 or 5 radiation-related toxicities were observed.

      Conclusions

      Hemithoracic pleural IMRT appears to have an acceptable toxicity profile in this interim analysis. Early intervention with steroids appears effective in avoiding severe toxicities of RP. This novel radiation technique has the potential to be part of a new multi-modality paradigm as a lung-sparing approach for the treatment of locally advanced MPM.

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