Pulmonary toxicity following IMRT after extrapleural pneumonectomy for malignant pleural mesothelioma

doi:10.1016/j.radonc.2009.03.011

Radiotherapy and Oncology

Volume 92, Issue 1, July 2009, Pages 96-99

https://doi.org/10.1016/j.radonc.2009.03.011 Get rights and content

Abstract

Background and purpose

The combination of chemotherapy, surgery, and radiotherapy has improved the prognosis for patients with malignant pleural mesothelioma (MPM). Intensity-modulated radiotherapy (IMRT) has allowed for an increase in dose to the pleural cavity and a reduction in radiation doses to organs at risk. The present study reports and analyses the incidence of fatal pulmonary toxicity in patients treated at Rigshospitalet, Copenhagen.

Materials and methods

Twenty-six patients were treated with induction chemotherapy followed by extrapleural pneumonectomy and IMRT between April 2003 and April 2006. The entire preoperative pleural surface area was treated to 50 Gy and areas with residual disease or close surgical margins were treated to 60 Gy in 30 fractions.

Results

The main toxicities were nausea, vomiting, esophagitis, dyspnea, and thrombocytopenia. One patient died from an intracranial hemorrhage during severe thrombocytopenia. Four patients (15%) experienced grade 5 lung toxicity, i.e. pneumonitis 19–40 days after the completion of radiotherapy. Patients with pneumonitis had a significantly larger lung volume fraction receiving 10 Gy or more (V10) (median: 60.3%, range 56.4–83.2%) compared to patients without pneumonitis (median: 52.6%, range: 25.6–80.3%) (p = 0.02). Mean lung dose (MLD) was also significantly higher in patients who developed pneumonitis (median 13.9 Gy, range: 13.6–14.2 Gy) than in patients who did not (median = 12.4 Gy, range: 8.4–15.4 Gy) (p = 0.04).

Conclusions

Significant differences in MLD and V10 for patients with fatal pulmonary toxicity compared to patients without fatal lung toxicity have been demonstrated. Based on the presented data local lung dose constraints have been modified in order to avoid unacceptable toxicity.

Section snippets

Methods and materials

Twenty-six patients with International Mesothelioma Interest Group (IMIG) stage T_1–3N₀M₀[9] were treated with trimodal therapy from April 2003 to April 2006. The treatment was approved by an institutional review board and written informed consent was obtained from all patients according to the standards of The Joint Commission. Induction chemotherapy with three to six courses of platinum-based combination chemotherapy was applied preoperatively at the local oncology department. All patients

Results

Patient median age was 61 years (range 45–69 years), 24 men and 2 women. Nine mesotheliomas (35%) were located in the left hemithorax, 17 (65%) in the right hemithorax. Histologically, 95% were epithelial and 5% of mixed origin. The preoperative staging procedure resulted in the following stage distribution: 4 patients in stage 1, 17 patients in stage 2, 4 patients in stage 3 and 1 patient in stage 4 (due to one needle track metastasis from thorascopy). All the 26 patients received induction

Discussion

Most of the previously applied normal lung tissue constraints in radiotherapy planning were based on the studies of lung toxicity after radiotherapy for lung cancer. The combination of intensive induction chemotherapy, primary extensive surgery, and large-field radiotherapy in trimodal therapy for MPM may, however, result in more serious pulmonary toxicity than initially expected.

In fact, the incidence of fatal radiation-induced pneumonitis in patients with MPM treated with trimodality therapy

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After initial reports with unacceptably high rates of severe and fatal pneumonitis, dose constraints to the uninvolved lung emerged, with most centers applying a mean dose of less than 8 Gy to the contralateral lung to enhance safety.11,24-28 A summary of select IMRT series in mesothelioma is shown in Table 1.29,30 SAKK17/04 was an international, multicenter, randomized, phase 2 trial conducted with radiation as the primary question.
Radiation therapy for mesothelioma remains challenging, as normal tissue toxicity limits the amount of radiation that can be safely delivered to the pleural surfaces, especially radiation dose to the contralateral lung. The physical properties of proton therapy result in better sparing of normal tissues when treating the pleura, both in the postpneumonectomy setting and the lung-intact setting. Compared with photon radiation, there are dramatic reductions in dose to the contralateral lung, heart, liver, kidneys, and stomach. However, the tissue heterogeneity in the thorax, organ motion, and potential for changing anatomy during the treatment course all present challenges to optimal irradiation with protons.
The clinical data underlying proton therapy in mesothelioma are reviewed here, including indications, advantages, and limitations.
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The role of radical radiotherapy in the management of malignant pleural mesothelioma: A systematic review
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The volume of contralateral lung receiving 5 Gy (V5) and the mean lung dose (MLD) have both been linked with the development of pneumonitis but only V20 has been demonstrated to have a statistically significant predictive association [27]. Data from these and other studies have informed recommended dose volume constraints in the post-EPP setting (Table 3) [25,27–29]. Following the publication of their toxicity data, researchers at the Dana-Faber Cancer Institute described a ‘restricted field’ IMRT technique which reportedly provides excellent target volume coverage within normal tissue dose constraints and greatly improves results for V5, V20 and MLD compared to standard IMRT [30].
Malignant pleural mesothelioma (MPM) is a devastating disease with limited treatment options and a dismal prognosis. Attempts to employ radical radiotherapy in this disease have been limited by the complex shape of the pleura and the dose restrictions necessitated by the close proximity of radiosensitive structures. Recent shifts towards a ‘lung sparing’ surgical approach in MPM have further heightened these challenges. The aim of this systematic review is to assess recent advances in radiotherapy planning and delivery, to ascertain how these developments have impacted on the feasibility of delivering photon-based, high-dose radiotherapy with radical intent in MPM. Three electronic databases were searched and a total of 249 articles reviewed. The challenge of generating high quality, practice-defining data for diseases such as MPM was highlighted by the identification of just two randomised studies. Much of the literature consisted of low quality, retrospective data with small cohorts and inconsistent reporting on radiotherapy techniques and dosimetry. Nevertheless, a number of prospective phase II studies were identified to suggest that radical doses of radiotherapy can be delivered safely after a lung sparing procedure in MPM, reporting encouraging survival data and acceptable levels of toxicity.
Radiotherapy for the treatment of malignant pleural mesothelioma
2017, The Lancet Oncology
Malignant pleural mesothelioma is an aggressive disease that continues to be associated with poor outcomes. Although, traditionally this disease is considered to be resistant to radiotherapy, more recent evidence suggests that radiotherapy can produce positive outcomes. Over the past 15 years, the development of new, highly conformal radiotherapy techniques, such as intensity-modulated radiation therapy (IMRT), has enabled investigators to optimise the delivery of high-dose radiotherapy to the whole of the hemithorax. Prospective single-arm trials have shown that the median survival of patients who have completed high-dose hemithoracic radiotherapy after extrapleural pneumonectomy could reach 23·9–39·4 months independent of the chemotherapeutic response, suggesting that IMRT could potentially have an intrinsic benefit to this subset of patients. These observations have led to a change in practice, with the introduction of adjuvant pleural IMRT after pleurectomy-decortication and the development of induction-accelerated hemithoracic IMRT followed by extrapleural pneumonectomy. This Review focuses on recent observations on the role of radiotherapy in the treatment of malignant pleural mesothelioma, with particular emphasis on the results of clinical trials that evaluate the role of high-dose hemithoracic radiotherapy.
Functional image guided radiation therapy planning in volumetric modulated arc therapy for patients with malignant pleural mesothelioma
2017, Advances in Radiation Oncology
To investigate the incorporation of functional lung image-derived low-attenuation area (LAA) based on 4-dimensional computed tomography (4D-CT) in volumetric modulated arc therapy (VMAT) planning for patients with malignant pleural mesothelioma (MPM) after extrapleural pneumonectomy.
Twelve patients with MPM after extrapleural pneumonectomy were included. The primarily affected side was the right in 6 patients and the left in 6 patients. LAA was generated from 4D-CT data according to CT values with a threshold of less than –860 Hounsfield units (HU). Functional lung image was defined as the area where LAA was excluded from contralateral lung image. Two radiation therapy plans were designed: (1) Plan C, conventional VMAT and (2) Plan F, functional VMAT plan based on the functional lung. Both plans were compared in each patient with respect to the following dosimetric parameters: fV20, V20, fV10, V10, fV5, and V5, the percentages of functional or contralateral lung volumes irradiated with >20 Gy, 10 Gy, or 5 Gy, respectively; functional mean lung dose (fMLD) and mean lung dose (MLD), the mean dose to the functional or contralateral lung, respectively; maximum dose to the cord; mean doses to the liver and heart; and planning target volume homogeneity index.
fV5 and MLD were significantly lower in Plan F (fV5, median 57.5% in Plan C vs 38.5% in Plan F, P < .01; MLD, median 7.0 Gy in Plan C vs 6.4 Gy in Plan F, P = .04). fV10, V5, and fMLD were also significantly lower in Plan F. Compared with Plan C, planning target volume homogeneity index and liver, heart, and cord doses were not significantly elevated in Plan F.
Significant reductions in fV5, fV10, fMLD, V5, and MLD were achieved with the functional image guided VMAT plan without negative effects on other factors. LAA-based functional image guided radiation therapy planning in VMAT is a feasible method to spare the functional lung in patients with MPM.
Radiation therapy for malignant pleural mesothelioma
2017, Cancer/Radiotherapie
The treatment of malignant pleural mesothelioma with radiation has always been a technical challenge. For many years, conventional radiation therapy was delivered after extrapleural pneumonectomy with acceptable results. Novel radiation treatment techniques, such as intensity modulated radiation therapy (IMRT) were introduced, but the early experience with IMRT demonstrated troubling toxicity. Recent reports from institutions have demonstrated that with greater experience, IMRT, both in the setting of extrapleural pneumonectomy or pleurectomy, can be delivered safely. A recent study, SAKK 17/04, questions the role of using radiation after extrapleural pneumonectomy.
La radiothérapie des mésothéliomes malins pleuraux a toujours été un défi technique. Longtemps, la radiothérapie classique a été délivrée après pneumonectomie extrapleurale avec des résultats acceptables. Les nouvelles techniques, comme la radiothérapie conformationnelle avec modulation d’intensité (RCMI), ont été proposées dans cette indication, mais les premières expériences de RCMI ont montré une toxicité inhabituelle. Cependant, les derniers rapports ont démontré qu’avec une bonne expérience la RCMI peut être indiquée, après pleuropneumonectomie élargie ou pleurectomie, avec une toxicité minime. Une étude récente, la SAKK 17/04, a évalué la place de la radiothérapie dans la prise en charge du mésothéliome malin pleural après pleuropneumonectomie élargie.

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MesotheliomaPulmonary toxicity following IMRT after extrapleural pneumonectomy for malignant pleural mesothelioma

Abstract

Background and purpose

Materials and methods

Results

Conclusions

Section snippets

Methods and materials

Results

Discussion

J Thorac Cardiovasc Surg

J Thorac Cardiovasc Surg

Int J Radiat Oncol Biol Phys

Lung Cancer

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Mesothelioma
Pulmonary toxicity following IMRT after extrapleural pneumonectomy for malignant pleural mesothelioma