Intensity-modulated radiotherapy following extrapleural pneumonectomy for the treatment of malignant mesothelioma: clinical implementation

doi:10.1016/S0360-3016(02)04150-0

International Journal of Radiation OncologyBiologyPhysics

Volume 55, Issue 3, 1 March 2003, Pages 606-616

https://doi.org/10.1016/S0360-3016(02)04150-0 Get rights and content

Abstract

Purpose: New insight into the extent of the target volume for the postoperative irradiation of malignant pleural mesothelioma as determined during surgery has indicated that standard conformal radiotherapy (IMRT) is not sufficient for curative treatment. We describe a novel technique for implementing intensity-modulated radiotherapy (IMRT) to deliver higher doses to treat the full extent of these complex target volumes.

Methods and Materials: After extrapleural pneumonectomy, 7 patients underwent simulation, treatment planning, and treatment with IMRT to the involved hemithorax and adjacent abdomen. The target volumes encompassed the entire operative bed, including the ipsilateral mediastinum, anterior pleural reflection, and ipsilateral pericardium and the insertion of the diaphragm and crura. These were extensively marked during surgery with radiopaque markers to facilitate target delineation.

Results: Setup uncertainty and respiratory-dependent motion were found to be small. Coverage of the planning target volume was very good, with the crus of the diaphragm the most difficult volume to irradiate. The radiation doses to normal structures were acceptable.

Conclusion: IMRT for treatment of malignant mesothelioma after extrapleural pneumonectomy results in more potentially curative doses to large, complex target volumes with acceptable doses to normal tissues. © 2003 Elsevier Science Inc.

Introduction

Although malignant mesothelioma of the thorax is an uncommon tumor, with an incidence of approximately 10 cases per million people annually in the United States (1), the incidence has been increasing. The disease represents a significant clinical problem in populations exposed to asbestos. The prognosis for this disease has been uniformly dismal, with several randomized studies showing equivalent survival rates when comparing multimodality treatment with pain management alone (2). Even such aggressive approaches as extrapleural pneumonectomy (EPP) and pleurectomy have not greatly affected outcome (3). Chemotherapy for this disease has been similarly disappointing. The most active regimens, those containing doxorubicin, have approximately 40% “response” rates, most of which are partial responses and of short duration.

The major problem encountered in the treatment of this disease is poor local disease control in the thorax, with disseminated disease seen only very late in its course 4, 5. The addition of postoperative radiotherapy (RT) to aggressive surgery has been attempted, but has been limited because of the proximity of dose-limiting structures 6, 7 such as the contralateral lung (tolerance ∼15–20 Gy [8]), heart (tolerance ∼45 Gy [9]), esophagus (tolerance ∼60 Gy [10]), and liver (tolerance ∼30 Gy [11]). Although the tolerance is mitigated by fractionation, the diffuse nature of most malignant mesotheliomas requires large volumes of these organs to be treated to very high radiation doses. The radiosensitivity of human mesothelioma (12) would make it a good candidate for a positive response to RT; however, the main reason why RT cannot prevent local recurrence is the limitation of doses owing to the tolerance of adjacent normal tissue. Thus, the addition of novel modalities, such as IMRT, aimed at improving local control, are likely to have the greatest impact on outcome.

This pilot study used IMRT to deliver therapeutically significant radiation doses. A dose of 50 Gy was delivered to a planning target volume (PTV) that included the entire hemithorax and adjacent abdomen, and a dose of 60 Gy was used for close or positive surgical margins while still sparing the nearby critical normal organs. IMRT has the flexibility that allows the delivery of dose distributions that conform to complicated convex and concave target volumes. IMRT has been deemed “advantageous for large, irregular targets with critical structures in close proximity” (13). These are exactly the conditions for which the treatment of malignant pleural mesothelioma (MPM) is planned.

Section snippets

Patient selection

Thoracic surgeons at The University of Texas M. D. Anderson Cancer Center identified potential candidates for this treatment method. Eligible patients must have undergone EPP for MPM and must have had no evidence of extrathoracic disease and no multiple discontinuous areas of chest wall involvement or invasion of mediastinal structures on CT of the chest and upper abdomen. Preoperatively, patients must have been first examined for general pulmonary (by spirometry and quantitative perfusion

Target volume delineation

Rational definition of the PTV required an understanding of both CTV motion and setup uncertainty. Two approaches were taken to assess CTV motion. First, by assessment of the ipsilateral CT motion artifacts and second, by comparison of CT scans obtained during inspiration and expiration. Figure 5 demonstrates that little motion of the ipsilateral hemithorax occurs with respiration. This is recognized by the absence of the artifact associated with respiratory motion and observed on the

Target volume delineation

Several previous papers have described radiation techniques for the treatment of MPM. Investigators at the Memorial Sloan-Kettering Cancer Center (MSKCC) described their technique in 1987 (14). Patients underwent subtotal pleurectomy followed by irradiation. The target volumes were similar to ours and included the ipsilateral hemithorax, mediastinum, and upper abdomen. At the time of pleurectomy, the diaphragm was clipped, but because no diaphragm resection was performed, the surgeons could not

Conclusion

Close cooperation among the surgeon, radiation oncologist, and radiation physicist can optimally delineate regions at high risk of recurrence of MPM. IMRT can deliver tumoricidal doses to the target volume and spare critical normal structures such as the heart, contralateral lung, and liver. Unfortunately, most of the ipsilateral kidney will be damaged by this technique. IMRT can be used to effect dose escalation up to 50 Gy to the hemithorax with boosts up to 60 Gy. Post-EPP IMRT also has

References (21)

V.W. Rusch
Pleurectomy/decortication and adjuvant therapy for malignant mesothelioma
Chest
(1993)
W. Gordon et al.
Radiation therapy in the management of patients with mesothelioma
Int J Radiat Oncol Biol Phys
(1982)
P.B. Bricout et al.
Computerized tomography scanning and the planning of high-dose radiotherapy for pleural mesotheliomaa report of five patients
Int J Radiat Oncol Biol Phys
(1981)
L.A. Dawson et al.
Partial irradiation of the liver
Semin Radiat Oncol
(2001)
S.L. Meeks et al.
Potential clinical efficacy of intensity-modulated conformal therapy
Int J Radiat Oncol Biol Phys
(1998)
G.J. Kutcher et al.
Technique for external beam treatment for mesothelioma
Int J Radiat Oncol Biol Phys
(1987)
M. Soubra et al.
Physical aspects of external beam radiotherapy for the treatment of malignant pleural mesothelioma
Int J Radiat Oncol Biol Phys
(1990)
V.W. Rusch et al.
A phase II trial of surgical resection and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma
J Thorac Cardiovasc Surg
(2001)
D.J. Sugarbaker et al.
Resection margins, extrapleural nodal status and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesotheliomaResults in 183 patients
J Thorac Cardiovasc Surg
(1999)
A. Ahamad et al.
Intensity-modulated radiation therapyA novel approach to the management of malignant pleural mesothelioma
Int J Radiat Oncol Biol Phys
(2003)

There are more references available in the full text version of this article.

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Clinical investigation: lungIntensity-modulated radiotherapy following extrapleural pneumonectomy for the treatment of malignant mesothelioma: clinical implementation

Abstract

Introduction

Section snippets

Patient selection

Target volume delineation

Target volume delineation

Conclusion

Chest

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Semin Radiat Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

J Thorac Cardiovasc Surg

J Thorac Cardiovasc Surg

Int J Radiat Oncol Biol Phys

Clinical investigation: lung
Intensity-modulated radiotherapy following extrapleural pneumonectomy for the treatment of malignant mesothelioma: clinical implementation