FATAL PNEUMONITIS ASSOCIATED WITH INTENSITY-MODULATED RADIATION THERAPY FOR MESOTHELIOMA

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1 RAPID COMMUNICATION FATAL PNEUMONITIS ASSOCIATED WITH INTENSITY-MODULATED RADIATION THERAPY FOR MESOTHELIOMA AARON M. ALLEN, M.D.,* MARIA CZERMINSKA, M.S.,* PASI A. JÄNNE, M.D., PH.D., DAVID J. SUGARBAKER, M.D., RAPHAEL BUENO, M.D., JAY R. HARRIS, M.D.,* LAURENCE COURT, PH.D.,* AND ELIZABETH H. BALDINI, M.D., M.P.H.* *Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women s Hospital, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women s Hospital, Boston, MA; Division of Thoracic Surgery, Brigham and Women s Hospital, and Harvard Medical School, Boston, MA 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/m 2 ). 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 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, %), 15.2 Gy (range, Gy), and 98.6% (range, %), respectively, as compared with 10.9% (range, %) (p 0.08), 12.9 Gy (range, Gy) (p 0.07), and 90% (range, %) (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 Elsevier Inc. Mesothelioma, Intensity-modulated radiation therapy, Pneumonitis, Mean lung dose. 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 Reprint requests to: Aaron Allen, M.D., Dana-Farber Cancer Institute, Department of Radiation Oncology, Dana L2, 44 Binney Street, Boston, MA Tel: (617) ; Fax: (617) ; [email protected] 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). Acknowledgments Special thanks to Drs. Harvey Mamon and Bruce Johnson for their critical reading of the manuscript. Received Mar 8, 2006, and in revised form Mar 15, Accepted for publication Mar 16, 2006.

2 Fatal pneumonitis associated with IMRT for mesothelioma A. M. ALLEN et al. 641 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 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. 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 intrapleural heated cisplatin (225 mg/m 2 ) chemotherapy at the time of surgery on a Brigham and Women s Hospital Phase II protocol. Dana-Farber Cancer Institute/Harvard Cancer Center Institutional Review Board approval was obtained to retrospectively review the records of these 13 patients. Systemic therapy Vogelzang et al. showed that patients with unresectable mesothelioma treated with cisplatin/pemetrexed chemotherapy enjoyed a 2-month prolongation in median survival compared with patients who were treated with cisplatin alone (1). Therefore, patients in this series were treated with 3 4 cycles of adjuvant cisplatin/pemetrexed chemotherapy after EPP. Chemotherapy was administered as published (1) with cisplatin given at 75 mg/m 2 and pemetrexed at 500 mg/m 2 every 21 days. Dose modifications were performed as previously published (1). Two patients received neoadjuvant chemotherapy one received 6 cycles of pemetrexed/cisplatin and the other received 2 cycles of pemetrexed/cisplatin. For the 10 patients who received adjuvant chemotherapy, the median time from completion of EPP to initiation of chemotherapy was 2.5 months (range 6 weeks to 3 months), and the median time from completion of chemotherapy to initiation of radiation therapy was 1 month (range 1 3 months). Twelve of 13 patients received intraoperative heated cisplatin chemotherapy (225 mg/m 2 ) on a Phase II institutional protocol. One patient developed renal insufficiency after treatment with intraoperative chemotherapy and was deemed unable to receive any intravenous chemotherapy. Patients treated in the adjuvant setting received at least 2 cycles of intravenous cisplatin/pemetrexed chemotherapy, 4 patients received 3 cycles of chemotherapy, and 1 patient received 4 cycles of chemotherapy. Restaging and radiotherapy planning At the time of the final cycle of chemotherapy, patients underwent a restaging PET/CT scan. Patients found to have distant disease in the abdomen or contralateral chest were deemed ineligible for radiation therapy. All patients deemed eligible for radiation therapy underwent CT simulation for radiation therapy planning. The patients were simulated with arms up and immobilized in a vac-loc bag with the use of a wing board (Med-Tec, Orange City, IA). A 1-cm bolus was placed over all thoracotomy scars for the planning scans. Patients were scanned at free breathing from the midneck to the pelvis to enable contouring and to assist with PET fusion. Contouring and target volume delineation The radiation oncologists (A.M.A., E.H.B.) drew the Clinical Target Volume 54 (CTV54) on each relevant slice from the lung apex to upper abdomen to include all areas of preoperative pleural surfaces. Volumes also included ipsilateral mediastinal lymph nodes and retrocrural space as defined by Ahamad et al. (7). When the CTV approximated critical structures such as spinal cord, heart, or liver, an alternative lower dose CTV (CTV 48) was defined to ensure appropriate sparing of critical structures. Thoracotomy scars were also included in the CTV54. Boost gross tumor volume (bgtv60) was defined based on areas of surgical concern such as positive margins or suspicion of residual disease and foci of PET-avidity on the restaging PET/CT done before radiation therapy. Normal tissue organs including liver, heart, esophagus, kidneys, contralateral lung, gastrointestinal tract, and spinal cord were also contoured on all relevant axial CT images. Dose prescription and optimization parameters The primary target volume CTV 54 was prescribed to 54 Gy. This was based on our previous institutional standard to give 54 Gy in the adjuvant setting for mesothelioma on the basis of published data for conventional radiation therapy (10). As described above, when normal tissue constraints were difficult to achieve (in the mediastinum or close to the spinal cord), a separate CTV structure was defined and prescribed to a dose of 48 Gy as we prioritized the normal tissue constraints ahead of CTV coverage in the optimization. Normal tissue tolerances We adhered to the normal tissue constraints from the published IMRT data (6, 7), and these are listed in Table 1. Two modifications to these were made. First, a constraint on the liver consisting of a mean liver dose of 31 Gy was added based on recent liver tolerance data (11). The contralateral lung was also limited to a mean lung dose (MLD) of less than 15 Gy as proposed by multiple Normal tissue Contralateral lung Table 1. Intensity-modulated radiotherapy optimization parameters Contralateral kidney V15 20% Liver Heart V45 30% V50 20% Spinal cord Dose volume constraints V20 20% and Mean lung dose 15 Gy V30 33% and Mean liver dose 31 Gy No portion may receive 60 Gy 90% must receive 45 Gy No portion may receive 50 Gy Abbreviation: V20 volume of lung receiving 20 Gy or more. Intensity-modulated radiation therapy optimization constraints for normal tissues.

3 642 Table 2. Patient characteristics (n 13) Age median (range) 66 (39 68) Gender BWH stage Laterality Histology Chemotherapy 11 Male 2 Female 2 Stage I 11 Stage III 7 Right 6 Left 8 Epithelial 5 Mixed 12 Intraoperative heated cisplatin 10 Adjuvant cisplatin/pemetrexed 2 neoadjuvant cisplatin/pemtrexed Abbreviation: BWH Brigham and Women s Hospital. Demographic and treatment details for 13 patients undergoing intensity-modulated radiation therapy. authors with respect to treatment of non small-cell lung cancer (NSCLC) (12, 13). After an initial death from pneumonitis, the remaining 2 patients in our series were planned with a more stringent lung criterion of MLD less than 9.5 Gy. Dose calculation and optimization were done using the ECLIPSE (Varian, Palo Alto, CA) treatment planning system, and tissue heterogeneity corrections (modified Batho) were employed. We planned and treated using sliding-window IMRT. Patientspecific quality assurance was carried out using a single ion chamber (Exradin A14) and film (EDR2, Kodak) placed in a solid water phantom. The departmental tolerance for the absolute dose agreement between ion chamber and calculation was 3%. Relative dose distributions were compared by overlaying the calculated and measured isodose curves using RIT4 software (RIT, Colorado Springs, CO). Departmental policy for cases where the absolute dose agreement was greater than 3%, but less than 5% was to critically examine the relative dose distributions, and then adjust the monitor units by % if appropriate. Dosimetric and spatial accuracy of our IMRT planning and delivery has been independently verified using the anthropomorphic head phantom from the Radiologic Physics Center (Houston, TX). All patients had dose volume histograms (DVHs) calculated for all target and normal tissue organs. Toxicities were defined by National Cancer Institute Common Toxicity Criteria v3.0 (14). Statistical comparisons were done using two-sided t test. RESULTS Thirteen patients with resected mesothelioma were treated with IMRT after EPP and adjuvant chemotherapy from December 2004 to September The median age of the patients was 66 years (range, years). There were 11 men and 2 women. The complete patient characteristics are listed in Table 2. Acute toxicity Thirty percent (4 of 13) of patients experienced National Cancer Institute Grade 3 nausea and vomiting and 23% (3 of 13) developed Grade 2 nausea and vomiting during radiation therapy treatment. One patient developed acute Grade 3 thrombocytopenia during radiation therapy. No other Grade 3 or greater acute toxicity was seen; and specifically, there were no complaints of dyspnea during treatment. Posttreatment toxicity After completion of therapy, 6 of 13 patients (46%) developed Grade 5 pneumonitis. All 6 patients required ventilatory support and subsequently died as a result of this toxicity. The median time to onset of this toxicity was 30 days (range 5 57 days) from the completion of IMRT. In all patients, the pneumonitis was accompanied by a radiographic appearance of diffuse interstitial infiltrate in the entire contralateral lung. Septic superinfection was present in 5 of the 6 patients. Three patients had late Grade 3 thrombocytopenia. The cause of death in all patients was respiratory failure. An autopsy was obtained for 2 patients. In both cases, the lungs revealed diffuse alveolar damage and dense fibrosis. As shown in Table 3, we compared various DVH metrics for the patients who developed pneumonitis with those who did not. These comparisons were limited by small numbers and in the case of V5, by the fact that all patients except 2 had values above 81%. The complete clinical and dosimetric details for all patients are shown in Table 4. The median V20 for the patients who developed pneumonitis was 17.6% (range, %) as compared with 10.9% (range, %) for the patients who did not develop pneumonitis (p 0.08) The median MLD was 15.2 Gy (range, Gy) for patients with pneumonitis as compared with 12.9 Gy (range, Gy) for the patients who did not develop pneumonitis (p 0.07). The median V5 for the patients who developed pneumonitis was 98.6% (range, %) as compared with 90% (range %) (p 0.20) for the patients who did not develop pneumonitis. Of the remaining 7 patients, 4 have Table 3. Comparison of dosimetric values of patients with and without fatal pneumonitis All patients* Patients with pneumonitis* Patients without pneumonitis* Comparison of with and without pneumonitis V % (3 24%) 17.6% ( %) 10.9% ( %) p 0.08 MLD 13.8 (7.3 17) Gy 15.2 ( ) Gy 12.9 ( ) Gy p 0.07 V5 92.4% (66 100%) 98.6% (81 100%) 90% ( %) p 0.20 Abbreviations: MLD mean lung dose; V20 volume of lung receiving 20 Gy or more; V5 volume of lung receiving 5 Gy or more. Comparison of the primary dose volume histogram metrics in patients who developed and did not develop pneumonitis. p values were calculated with Student t test. * Values are expressed as median (range).

4 Fatal pneumonitis associated with IMRT for mesothelioma A. M. ALLEN et al. 643 Table 4. Dose volume parameters and pneumonitis for 13 patients treated with intensity-modulated radiation therapy for mesothelioma Patient Goals % Side Right Left Left Right Left Right Left Left Left Right Right Pneumonitis N N Y Y N N N Y Y Y Y CTV Vol (cc s) Boost vol (cc) Contralateral lung V Mean dose (Gy) V Liver V Mean dose (Gy) Esophagus V Heart V V Contralateral kidney V Technique No. of beam directions No. of beams Patient Goals % Side Right Right Pneumonitis N N CTV Vol (cc s) Boost vol (cc) 8.1 Contralateral Lung V Mean dose (Gy) < V Liver V Mean dose (Gy) Esophagus V Heart V V Contralateral kidney V Technique No. of beam directions 9 9 No. of beams Abbreviations: CTV clinical target volume; V20 volume of lung receiving 20 Gy or more; N no; Y yes. Full dose volume details on all 13 patients. Goals were as outlines. Numbers in bold reflect numbers in excess of goals. died of progressive mesothelioma with a median survival of 11 months from diagnosis (range, months). Three patients remain alive without evidence of disease with a median follow-up of 16 months (range, 15 to 17 months). The 2 patients who were treated and had a MLD 9.5 are alive and without recurrence or toxicity 7 months after treatment. 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

5 644 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 before IMRT may have predisposed the patients in this series to develop combined modality pneumonitis. There is no published literature regarding the combination of intrapleural chemotherapy and radiation therapy. However, a possible explanation is that intrapleural chemotherapy increases the levels of circulating proinflammatory cytokines, which predisposed these patients to develop pneumonitis. In the literature describing intrapleural cisplatin chemotherapy, there are no reported increases in lung toxicity (15 17). The second possible explanation is an interaction between systemic chemotherapy and radiation therapy such as has been seen for gemcitabine and radiation therapy for the treatment of NSCLC (18 20). Pemetrexed and cisplatin are known to be radiosensitizing agents (21); however, a recent experience in NSCLC of concurrent radiation therapy and pemetrexed-based chemotherapy reported a low incidence of radiation pneumonitis (22). Perhaps the most likely explanation for the increased pulmonary toxicity is the dose volume effects of the IMRT on the contralateral lung after pneumonectomy. It is unclear, however, which of the various lung DVH metrics best predicts for pneumonitis after pneumonectomy. Limited comparable data from treatment of NSCLC are available because few patients with NSCLC are irradiated after a total pneumonectomy. However, three separate analyses of single lung toxicity modeling all have demonstrated a 10% incidence of pneumonitis for patients treated with MLD 15 Gy (12, 23, 24). In another study, no increased incidence of pneumonitis was seen in patients who underwent pneumonectomy followed by postoperative radiation therapy compared with patients who received radiation therapy without surgery (25). These data suggest that surgical resection may not significantly influence the tolerance of the remaining lung to radiation therapy when conventional techniques are used. However, the comparison is limited by the volume of radiotherapy in NSCLC and the differences between EPP and pneumonectomy. This would seem to suggest that the phenomenon, which occurs with IMRT, is fundamentally different than what has been studied previously. To assess the importance of the various DVH metrics (V20, MLD, and V5), we compared these metrics for the patients who developed pneumonitis with those who did not (Table 3). These comparisons were limited by small numbers and, in the case of V5, by the fact that all but 2 patients had values above 81%. We found that although all of the values on average were higher for patients with pneumonitis than those without pneumonitis, none of the differences were statistically significant. All but 3 patients in our series had a V20 of less than 20%, which should have been safe (the other 3 had V20 values of 21%, 22%, and 25%); however, an examination of the entire DVH curve shows that in our patients, because of IMRT delivery, almost the entire contralateral lung received a very low dose of irradiation. This is a phenomenon not usually seen with conventional radiation techniques. To assess the importance of this extent of low-dose lung irradiation, it is perhaps reasonable to compare this experience to experience with total body irradiation in which large portions of the lungs also receive low-dose irradiation. In a recent review of patients treated with total body irradiation, a statistically significant higher rate of radiation pneumonitis was seen for patients receiving an MLD greater than 9.5 Gy compared with those receiving 9.5 Gy (14% vs. 4%) (26). Even though this level of MLD is far lower than typically thought to be significant, in a setting of large volume irradiation of lung, an MLD of 9 may be more appropriate as tolerance than an MLD of 15. A similar criterion has been proposed by Ahamad et al. (5). Similarly, perhaps V20 is not the correct metric to use when considering techniques that deliver low-dose irradiation to large volumes of remaining lung tissue. In support of that theory, a large multi-institutional retrospective series of lung toxicity data found V13 to be a better predictor of pneumonitis than V20 or even MLD (27). More recently, a secondary analysis of a dose escalation study in patients with NSCLC showed that V5 was an even better predictor of pneumonitis than V20 or MLD (28). These data suggest that perhaps it is not only the amount of lung treated that is the critical metric, but also the amount of lung spared completely from irradiation that determines the risk of toxicity. The latter may be particularly important when using IMRT in treating mesothelioma. The early experience in the treatment of esophageal cancer with IMRT and three-dimensional conformal radiation therapy supports this possibility. A recent series showed a 16% incidence of postoperative pulmonary complications in patients treated to Gy, and the volume of lung spared at least 5 Gy was the most significant dose volume metric predictive of postoperative pulmonary complications (29). Another study of IMRT for NSCLC also produced a fatal pneumonitis that was not expected (30). When we retrospectively examined the parameter V5 for our patients treated with IMRT, we found that the majority of patients in our series had a V5 greater than 90%. These high V5 values may, in fact, have been a key contributor to the observed pulmonary toxicity either instead of or along with the MLD values greater than 9.5 Gy. In addition, our prescription dose of 54 Gy was higher than proposed by other investigators. However, we feel the V5, MLD, and V20 metrics are more relevant than the absolute total dose in predicting pneumonitis, although all of these metrics are interrelated. In conclusion, using the dosimetric parameters in our study, IMRT treatment for mesothelioma after EPP and adjuvant chemotherapy has produced a high rate of fatal pneumonitis. We therefore recommend caution in the utilization of this technique until there is a clearer understanding of the dose volume effects created by IMRT for this patient population. Although not established, our data suggest that, especially with IMRT, metrics such as V5 and MLD should be used in addition to V20 to determine tolerance levels in future patients treated with IMRT for mesothelioma. In particular, our data

6 suggest the need to consider whether low doses of radiation therapy given to the remaining lung are dangerous when using standard tolerance limits for MLD and V20. This experience should also serve to caution investigators who seek to use IMRT in yet unproven treatment settings (such as the treatment of NSCLC) as unexpected toxicities may arise. Nevertheless, the sparing of normal tissues, such as the heart and liver, and the increased coverage of the target volume that IMRT allows make this technique very appealing for the adjuvant treatment of mesothelioma after EPP. At our institution, we plan to conduct a Phase I trial of IMRT with revised, more stringent lung dose constraints.