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Fatal pneumonitis associated with intensity-modulated radiation therapy for mesothelioma

https://doi.org/10.1016/j.ijrobp.2006.03.012Get rights and content

Purpose: To describe the initial experience at Dana-Farber Cancer Institute/Brigham and Women’s Hospital with intensity-modulated radiation therapy (IMRT) as adjuvant therapy after extrapleural pneumonectomy (EPP) and adjuvant chemotherapy.

Methods and Materials: The medical records of patients treated with IMRT after EPP and adjuvant chemotherapy were retrospectively reviewed. IMRT was given to a dose of 54 Gy to the clinical target volume in 1.8 Gy daily fractions. Treatment was delivered with a dynamic multileaf collimator using a sliding window technique. Eleven of 13 patients received heated intraoperative cisplatin chemotherapy (225 mg/m2). Two patients received neoadjuvant intravenous cisplatin/pemetrexed, and 10 patients received adjuvant cisplatin/pemetrexed chemotherapy after EPP but before radiation therapy. All patients received at least 2 cycles of intravenous chemotherapy. The contralateral lung was limited to a V20 (volume of lung receiving 20 Gy or more) of 20% and a mean lung dose (MLD) of 15 Gy. All patients underwent fluorodeoxyglucose positron emission tomography (FDG-PET) for staging, and any FDG-avid areas in the hemithorax were given a simultaneous boost of radiotherapy to 60 Gy. Statistical comparisons were done using two-sided t test.

Results: Thirteen patients were treated with IMRT from December 2004 to September 2005. Six patients developed fatal pneumonitis after treatment. The median time from completion of IMRT to the onset of radiation pneumonitis was 30 days (range 5–57 days). Thirty percent of patients (4 of 13) developed acute Grade 3 nausea and vomiting. One patient developed acute Grade 3 thrombocytopenia. The median V20, MLD, and V5 (volume of lung receiving 5 Gy or more) for the patients who developed pneumonitis was 17.6% (range, 15.3–22.3%), 15.2 Gy (range, 13.3–17 Gy), and 98.6% (range, 81–100%), respectively, as compared with 10.9% (range, 5.5–24.7%) (p = 0.08), 12.9 Gy (range, 8.7–16.9 Gy) (p = 0.07), and 90% (range, 66–98.3%) (p = 0.20), respectively, for the patients who did not develop pneumonitis.

Conclusions: Intensity-modulated RT treatment for mesothelioma after EPP and adjuvant chemotherapy resulted in a high rate of fatal pneumonitis when standard dose parameters were used. We therefore recommend caution in the utilization of this technique. Our data suggest that with IMRT, metrics such as V5 and MLD should be considered in addition to V20 to determine tolerance levels in future patients.

Introduction

Pleural mesothelioma is a largely fatal disease with an aggressive clinical course and a high mortality rate using currently available therapy. Median survival is 12 months (1). Death is often caused by local progression ultimately resulting in respiratory failure. There is no clear standard of care for mesothelioma, and the relatively low incidence of the disease has made the conduct of randomized controlled studies with adequate numbers of patients difficult.

A minority of patients with mesothelioma have disease limited to the chest and are therefore candidates for aggressive surgical resection. Extrapleural pneumonectomy (EPP) has been associated with better local control than pleurectomy/decortication (2, 3). However, even with EPP, 80% of patients experience local tumor progression (2). Because of this, aggressive combined approaches utilizing adjuvant chemotherapy and conventional radiation therapy (trimodality therapy) have been attempted. In our earlier experience with trimodality therapy including EPP, hemithoracic radiation, and chemotherapy, the 5-year survival rate was only 14% (4). Therefore, new avenues for improvements in local and systemic therapies have been attempted.

In 2003, preliminary results were published describing the utilization of intensity-modulated radiotherapy (IMRT) in the adjuvant setting after EPP. These preliminary results suggested that IMRT could be safely administered and could provide a local control rate of greater than 80% (5, 6, 7), far better than other series of adjuvant radiation therapy using conventional techniques (8, 9). Based on these promising results, this technique was initiated at the Dana-Farber Cancer Institute/Brigham and Women’s Hospital. In this report we describe our initial experience, which demonstrated a high treatment-related mortality rate from pneumonitis.

Section snippets

Methods and materials

From December 2004 to August 2005, 13 patients were treated with IMRT after EPP and adjuvant chemotherapy at the Dana-Farber Cancer Institute/Brigham and Women’s Hospital. All patients underwent preoperative mediastinoscopy, computed tomography (CT), magnetic resonance imaging, and positron emission tomography (PET) scans to determine resectability. Surgeons in the division of thoracic surgery at Brigham and Women’s Hospital performed an EPP. Twelve of 13 patients received intraoperative

Results

Thirteen patients with resected mesothelioma were treated with IMRT after EPP and adjuvant chemotherapy from December 2004 to September 2005. The median age of the patients was 66 years (range, 39–68 years). There were 11 men and 2 women. The complete patient characteristics are listed in Table 2.

Discussion

This small series demonstrates an unacceptably high rate of fatal pneumonitis after EPP with intraoperative cisplatin, adjuvant cisplatin/pemetrexed, and IMRT to a dose of 54 Gy delivered to the hemithorax.

We have sought to determine why this regimen was so much more toxic than expected. There are several possible explanations, and the true answer may lie in one or more of the following possibilities. The first possible explanation is that the addition of intrapleural or systemic chemotherapy

Acknowledgments

Special thanks to Drs. Harvey Mamon and Bruce Johnson for their critical reading of the manuscript.

References (30)

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