Hemithoracic Intensity-modulated Radiation Therapy Research Articles

Adjuvant Radiation Therapy for Pleural Mesothelioma after Extrapleural Pneumonectomy (EPP) or Pleurectomy and Decortication (P+D)

The optimal treatment sequence for localized malignant pleural mesothelioma (MPM) is controversial. We hypothesized that pleurectomy and decortication (P+D) followed by adjuvant intensity modulated radiation therapy (IMRT) has equivalent cancer control with less morbidity than extrapleural pneumonectomy (EPP) followed by adjuvant radiation therapy (RT). Forty-four patients treated with curative intent surgery and adjuvant RT for MPM at a single institution were included. Prior to September 2013, patients were treated with EPP followed by adjuvant RT (n = 24, 54%). After September 2013, standard treatment was P+D followed by adjuvant IMRT (n = 20, 45%). We compared oncologic outcomes and toxicities (CTCAE version 5.0) between these two approaches. Median age at diagnosis was 64 years (range 26-76); patients receiving EPP were significantly younger (median age 60 vs. 70, p<0.01). Most patients were AJCC 8th edition clinical stage T1 (80%) and N0 (91%). Thirty-seven patients (84%) received neoadjuvant chemotherapy. At surgery, pathologic T stage was most commonly T3 (64%), with 30% node positive. Forty-two patients (95%) had epithelioid histology at surgery, and the remaining two had biphasic histology (5%). Median total RT dose to the entire pleura was 45 Gy (range 30-60 Gy), delivered over a median 27 fractions (range 20-33). Median follow-up for the entire cohort was 3.9 years (range 0.6-20.0 years). Median OS was 2.6 years for P+D compared to 1.1 years for EPP (HR: 0.52, 95% CI: 0.25-1.09, p = .08). Two-year OS was 63% for P+D versus 21% for EPP. On univariate analysis, male sex, pre-operative FEV1% <80, and clinically positive nodes were significantly associated with risk of death. There was no difference in locoregional control (LRC) or progression-free survival (PFS) between P+D and EPP. LRC at 2 and 5 years for the entire cohort was 48% and 39%. PFS at 2 and 5 years was 34% and 17%. Acute Grade 2+ pneumonitis was seen in 0% of EPP patients compared to 35% for P+D, with one grade 3 (5%), one grade 4 (5%), and no grade 5 (0%) pneumonitis. Mean lung dose was significantly associated with development of any grade pneumonitis (odds ratio: 1.46, 95% CI: 1.02-2.11, p = 0.04). Patients who developed pneumonitis had a mean total lung mean dose of 20.4 Gy, compared to 12.9 Gy in those who did not. Total lung V20% was also significantly associated with development of any grade pneumonitis (odds ratio: 1.11, 95% CI: 1.01-1.22, p = 0.03). Mean total lung V20% was 38% for those who developed pneumonitis, compared to 20% for those who did not. FEV1% declined by 27% after P+D and 32% after EPP, while DLCO% declined by 22% after P+D and 28% after EPP. Modern treatment with pleurectomy and decortication followed by adjuvant hemithoracic IMRT appears to provide favorable survival compared to EPP followed by RT, though more non-fatal pneumonitis was seen after P+D with adjuvant IMRT.

MS 06.05 The Use of Adjuvant IMRT after Pleurectomy/Decortication

MS 06.05 The Use of Adjuvant IMRT after Pleurectomy/Decortication

Intensity modulated radiation therapy after extra-pleural pneumonectomy for malignant pleural mesothelioma is feasible without fatal pulmonary toxicity and provides good survival.

To analyze patterns of failure, toxicity, relapse-free survival (RFS), and overall survival (OS) in malignant pleural mesothelioma (MPM) patients treated with intensity-modulated radiation therapy following extrapleural pneumonectomy (EPP). We reviewed 18 charts of patients with MPM from 2005 to 2014 who underwent EPP followed by hemithoracic intensity-modulated radiation therapy. Intensity-modulated radiation therapy dose delivery adhered to published lung dose constraints. Kaplan-Meier curves were used to assess the RFS and OS. Median survival times are reported for both RFS and OS. Median age was 65 years (range: 40-76 years). Chemotherapy was administered in four neo-adjuvant and seven adjuvant patients. Pathological American Joint Committee on Cancer stages II, III, IV, surgical margin, lympho-vascular space, pericardium, and chest wall involvement were seen in 3, 12, 3, 9, 7, 12 and 3 patients, respectively. The majority of the patients received 45 Gy in 25 fractions. The mean lung dose was 7.14 Gy (range: 5 Gy-9.3 Gy). The mean V20 was 2.23%. At a median follow-up of 3 years, eight patients were alive (44%); 10 experienced relapse (56%). Median RFS and OS were 24.4 months (95% CI: >16.3 months) and 38.2 months (95% CI: 17.4-78.1 months), respectively. Acute toxicities were fatigue, dermatitis, nausea, esophagitis/dysphagia, cough, and dyspnea on exertion. No grade III, IV, or fatal pulmonary toxicities were observed. Intensity-modulated radiation therapy following EPP for MPM resulted in RFS and OS comparable to the published literature without significant toxicity.

Geometric dose prediction model for hemithoracic intensity-modulated radiation therapy in mesothelioma patients with two intact lungs.

The presence of two intact lungs makes it challenging to reach a tumoricidal dose with hemithoracic pleural intensity‐modulated radiation therapy (IMRT) in patients with malignant pleural mesothelioma (MPM) who underwent pleurectomy/decortications or have unresectable disease. We developed an anatomy‐based model to predict attainable prescription dose before starting optimization. Fifty‐six clinically delivered IMRT plans were analyzed regarding correlation of prescription dose and individual and total lung volumes, planning target volume (PTV), ipsilateral normal lung volume and ratios: contralateral/ipsilateral lung (CIVR); contralateral lung/PTV (CPVR); ipsilateral lung /PTV (IPVR); ipsilateral normal lung /total lung (INTLVR); ipsilateral normal lung/PTV (INLPVR). Spearman's rank correlation and Fisher's exact test were used. Correlation between mean ipsilateral lung dose (MILD) and these volume ratios and between prescription dose and single lung mean doses were studied. The prediction models were validated in 23 subsequent MPM patients. CIVR showed the strongest correlation with dose (R=0.603,p<0.001) and accurately predicted prescription dose in the validation cases. INLPVR and MILD as well as MILD and prescription dose were significantly correlated (R=‐0.784,p<0.001 and R=0.554,p<0.001, respectively) in the training and validation cases. Parameters obtainable directly from planning scan anatomy predict achievable prescription doses for hemithoracic IMRT treatment of MPM patients with two intact lungs.PACS number(s): 87.55.de, 87.55.dk

Impact of induction therapy on postoperative outcome after extrapleural pneumonectomy for malignant pleural mesothelioma: does induction-accelerated hemithoracic radiation increase the surgical risk?

Patients with malignant pleural mesothelioma (MPM) eligible for extrapleural pneumonectomy (EPP) may benefit from induction chemotherapy (CT) as historically described, or from induction-accelerated hemithoracic intensity-modulated radiation therapy (IMRT) as a potential alternative. However, the impact of the type of induction therapy on postoperative morbidity and mortality remains unknown. We performed a retrospective study including every patient who underwent EPP for MPM in our institution between January 2001 and December 2014. Patients without induction treatment (n = 7) or undergoing both induction CT and IMRT (n = 2) were then excluded. The remaining patients (study group) were divided according to the type of induction treatment in Group 1-CT and Group 2-IMRT. Major complications were defined by complications of Grade 3 or higher according to the National Cancer Institute Common Terminology Criteria for Adverse Events 4.0 guidelines. Red blood cell (RBC) transfusion was analysed as a number of packs, and dichotomized as <3 vs ≥3 packs. Plasma and platelet transfusion were analysed as a number of units, and dichotomized as no transfusion versus any plasma or platelet transfusion. Altogether, 126 patients (mean age 61.3 ± 8.1 years, males 82.5%, right side 60.3%, 90-day mortality rate 4.8%) accounted for the study group. Sixty-four patients were included in Group 1-CT and 62 patients were included in Group 2-IMRT. When compared with Group 1-CT, Group 2-IMRT was characterized by older patients (59.3 ± 9.2 vs 63.3 ± 8.3 years, P = 0.012), more right-sided resections (46.8 vs 74.1%, P = 0.003), more advanced disease (pathological stage IV: 28.1 vs 53.2%, P = 0.007), less RBC transfusions (5.1 ± 3.0 vs 3.0 ± 2.4 packs, P < 0.001), less plasma or platelet transfusions (31.2 vs 9.6%, P = 0.005) and similar rate of major complications (29.6 vs 35.4%, P = 0.614). The 90-day mortality rate was 6.2% in Group 1-CT (n = 4) and 3.2% in Group 2-RT (n = 2, P = 0.680). Induction with IMRT was significantly associated with a decreased risk of transfusion with RBCs [odds ratio (OR) = 0.10, 95% confidence interval (CI) 0.04-0.23, P < 0.001] as well as plasma and platelets (OR = 0.25, 95% CI 0.086-0.67, P = 0.008). In this large single-centre series of EPP for MPM, the implementation of induction IMRT was not associated with any significant increase in the surgical risks above and beyond induction CT. The switch from induction CT to induction IMRT was associated with resection in older patients with more advanced tumours, less transfusion requirements, comparable postoperative morbidity and 90-day mortality.

Accelerated hemithoracic radiation followed by extrapleural pneumonectomy for malignant pleural mesothelioma

ObjectiveTo evaluate a new protocol of accelerated hemithoracic intensity-modulated radiation therapy (IMRT) followed by extrapleural pneumonectomy (EPP) for patients with resectable malignant pleural mesothelioma (MPM). MethodsA total of 25 Gy of radiation was delivered in 5 daily fractions over 1 week to the entire ipsilateral hemithorax with concomitant boost of 5 Gy to volumes at high risk based on computed tomography and positron emission tomography scan findings. EPP was performed at 6 ± 2 days after the end of radiation therapy. Adjuvant chemotherapy was offered to patients with ypN2 disease. ResultsA total of 62 patients were included between November 2008 and October 2014. One patient died in the hospital 2 months after EPP, for an operative mortality of 1.6%, and 2 died after discharged from the hospital for an overall treatment-related mortality (grade 5 toxicity) of 4.8%. Twenty-four patients (39%) developed grade 3 to 5 (grade 3+) complications. On final pathology, 94% of the patients were stage III or IV, and 52% had ypN2 disease. The median survival for all patients as an intention-to-treat analysis was 36 months. The median overall survival and disease-free survival was 51 and 47 months, respectively, in epithelial subtypes, compared with 10 and 8 months in biphasic subtypes (P = .001). Ipsilateral chest recurrence occurred in 8 patients. ConclusionsAccelerated hemithoracic IMRT followed by EPP has become our preferred approach for resectable MPM. The results have been encouraging in patients with epithelial subtype.

Hemithoracic Intensity Modulated Radiation Therapy After Pleurectomy/Decortication for Malignant Pleural Mesothelioma: Toxicity, Patterns of Failure, and a Matched Survival Analysis

To investigate safety, efficacy, and recurrence after hemithoracic intensity modulated radiation therapy after pleurectomy/decortication (PD-IMRT) and after extrapleural pneumonectomy (EPP-IMRT). In 2009-2013, 24 patients with mesothelioma underwent PD-IMRT to the involved hemithorax to a dose of 45 Gy, with an optional integrated boost; 22 also received chemotherapy. Toxicity was scored with the Common Terminology Criteria for Adverse Events v4.0. Pulmonary function was compared at baseline, after surgery, and after IMRT. Kaplan-Meier analysis was used to calculate overall survival (OS), progression-free survival (PFS), time to locoregional failure, and time to distant metastasis. Failures were in-field, marginal, or out of field. Outcomes were compared with those of 24 patients, matched for age, nodal status, performance status, and chemotherapy, who had received EPP-IMRT. Median follow-up time was 12.2 months. Grade 3 toxicity rates were 8% skin and 8% pulmonary. Pulmonary function declined from baseline to after surgery (by 21% for forced vital capacity, 16% for forced expiratory volume in 1 second, and 19% for lung diffusion of carbon monoxide [P for all = .01]) and declined still further after IMRT (by 31% for forced vital capacity [P=.02], 25% for forced expiratory volume in 1 second [P=.01], and 30% for lung diffusion of carbon monoxide [P=.01]). The OS and PFS rates were 76% and 67%, respectively, at 1 year and 56% and 34% at 2 years. Median OS (28.4 vs 14.2 months, P=.04) and median PFS (16.4 vs 8.2 months, P=.01) favored PD-IMRT versus EPP-IMRT. No differences were found in grade 4-5 toxicity (0 of 24 vs 3 of 24, P=.23), median time to locoregional failure (18.7 months vs not reached, P not calculable), or median time to distant metastasis (18.8 vs 11.8 months, P=.12). Hemithoracic intensity modulated radiation therapy after pleurectomy/decortication produced little high-grade toxicity but led to progressive declines in pulmonary function; OS and PFS were better in PD-IMRT compared with EPP-IMRT.

Postoperative Hemithoracic Intensity Modulated Radiation Therapy (IMRT) With an Optional Integrated Boost for Malignant Pleural Mesothelioma: Toxicity, Patterns of Failure, and a Matched Survival Analysis

Hemithoracic intensity-modulated radiation therapy (IMRT) after pleurectomy/decortication (PD) is a novel paradigm for which there is limited data. We investigated the safety, efficacy and recurrence patterns in patients treated with this technique. We then compared the treatment related toxicity and survival of this cohort to patients treated with postoperative IMRT after extrapleural pneumonectomy (EPP).

A Feasibility Study Evaluating Surgery for Mesothelioma After Radiation Therapy: The “SMART” Approach for Resectable Malignant Pleural Mesothelioma

We developed an innovative approach for malignant pleural mesothelioma (MPM) with a short accelerated course of high-dose hemithoracic intensity-modulated radiation therapy (IMRT) followed by extrapleural pneumonectomy (EPP). This phase I/II study assessed the feasibility of Surgery for Mesothelioma After Radiation Therapy (SMART). All resectable clinical T1-3N0M0 histologically proven, previously untreated MPMs were eligible. Patients received 25 Gy in five daily fractions during 1 week to the entire ipsilateral hemithorax with concomitant 5 Gy boost to areas at risk followed by EPP within 1 week of completing neoadjuvant IMRT. Adjuvant chemotherapy was offered to ypN2 patients on final pathologic findings. The primary end point was treatment-related mortality and secondary end points were overall survival, disease-free survival, treatment-related morbidity, and patterns of failure. Targeted accrual of 25 patients was completed between November 2008 and October 2012. All patients completed SMART. IMRT was well tolerated with no grade 3+ toxicities. EPP was performed 6 ± 2 days after completing IMRT without any perioperative mortality. Thirteen patients developed grade 3+ surgical complications. One patient (4%) died from treatment-related toxicity (empyema) during follow-up. All but one patient had stage III or IV disease on final pathologic findings. Five of 13 ypN2 patients received adjuvant chemotherapy. After a median follow-up of 23 months (range, 6-51), the cumulative 3-year survival reached 84% in epithelial subtypes compared with 13% in biphasic subtypes (p = 0.0002). SMART is feasible in resectable MPM patients. This innovative protocol presents encouraging results and supports future studies looking at long-term outcome in patients with epithelial subtypes.

Accelerated hypofractionated hemithoracic intensity modulated radiation therapy (IMRT) followed by extrapleural pneumonectomy (EPP) for malignant pleural mesothelioma (MPM): Results of a phase I/II study.

7526 Background: We developed a protocol with accelerated hypofractionated hemithoracic IMRT followed by EPP for MPM. Advantages include optimal delivery of radiation to the whole tumor bed in a short period limiting the risk of viable tumor cell spread during surgery. Methods: Patients with resectable clinical T1-3N0M0 histology proven MPM were eligible for the study. 25 Gy in 5 daily fractions over 1 week was delivered to the entire ipsilateral hemithorax by IMRT with concomitant boost of 5 Gy to volumes at high risk based on CT and PET scan findings. EPP was performed one week after the end of radiation. Adjuvant chemotherapy was offered to patients with ypN2 on final pathology. The primary end-point was treatment related mortality. Secondary endpoint included overall survival and disease-free survival (DFS). Initial sites of recurrence were also recorded. Results: Twenty five patients were accrued between 11/2008 and 10/2012. Patients had a median age of 64 years (range, 45-75), 76% were males, 64% had epithelioid histology. All patients completed IMRT and EPP. IMRT was well tolerated with no grade 3-5 toxicity. EPP was performed 6±2 days after completion of IMRT. Surgical complications occurred in 18 patients. One patient died from empyema at 88 days. All but one patient (stage IB) had stage III (n=11) or IV (n=13) disease on final pathology. Five out of 13 patients with ypN2 disease underwent adjuvant chemotherapy. After a median follow-up of 19 months (range, 3-51), the estimated 3-year survival reached 62%. Survival was significantly better in epithelioid compared to biphasic pathologic subtypes (83% survival at 3 years vs 19%, respectively; p=0.004). 14 patients remain disease free after a median follow-up of 17 months (range, 3-37). 2-year DFS was 85% in stage III and 37% in stage IV disease (p=0.03). Recurrences occurred in the ipsilateral chest only (n=2), ipsilateral chest and distant sites (n=2), and distant sites only (n=6). Conclusions: Accelerated hypofractionated hemithoracic IMRT followed by EPP is feasible. This treatment could improve survival in selected patients with epithelial subtype. Clinical trial information: NCT00797719.

Patterns of Failure, Toxicity, and Survival after Extrapleural Pneumonectomy and Hemithoracic Intensity-Modulated Radiation Therapy for Malignant Pleural Mesothelioma

We investigated safety, efficacy, and recurrence after postoperative hemithoracic intensity-modulated radiation therapy (IMRT) in patients with malignant pleural mesothelioma treated with extrapleural pneumonectomy (EPP), during the past decade at a single institution. In 2001-2011, 136 consecutive patients with malignant pleural mesothelioma underwent EPP with planned adjuvant IMRT. Eighty-six patients (64%) underwent hemithoracic IMRT; the rest were not eligible because of postoperative complications, disease progression, or poor performance status. We assessed toxicity, survival, and patterns of failure in these 86 patients. Toxicity was scored with the Common Terminology Criteria for Adverse Events version 4.0; survival outcomes were estimated with the Kaplan-Meier method; and locoregional patterns of failure were classified as in-field, marginal, or out-of-field. Risk factors related to survival were identified by univariate and multivariate Cox regression analysis. Median overall survival time for all 86 patients receiving IMRT was 14.7 months. Toxicity rates of grade of 3 or more were: skin 17%, lung 12%, heart 2.3%, and gastrointestinal toxicity 16%. Five patients experienced grade 5 pulmonary toxicity. Rates of locoregional recurrence-free survival, distant metastasis-free survival, and overall survival (OS) were 88%, 55%, and 55% at 1 year and 71%, 40%, and 32% at 2 years. On multivariate analysis, pretreatment forced expiratory volume in 1 second, nonepithelioid histology, and nodal status were associated with distant metastasis-free survival and OS. IMRT after EPP is associated with low rates of locoregional recurrence, though some patients experience life-threatening lung toxicity. Tumor histology and nodal status can be helpful in identifying patients for this aggressive treatment.

Hemithoracic Intensity-modulated Radiotherapy Using Helical Tomotherapy for Patients after Extrapleural Pneumonectomy for Malignant Pleural Mesothelioma

Postoperative hemithoracic irradiation is regarded as an important part of the curative treatment for resectable malignant pleural mesothelioma (MPM). Because the clinical target volume in postoperative MPM is irregular and surrounded by dose-limiting critical structures, intensity-modulated radiation therapy (IMRT) is thought to be suitable. However, postoperative hemithoracic IMRT remains experimental due to a high incidence of fatal pneumonitis. Therefore, a Phase I dose escalation study for hemithoracic IMRT using helical tomotherapy was planned, and the results of the first three patients are herein reported because this technique may provide benefits to such patients. For 3 patients with postoperative MPM, who were treated by extrapleural pneumonectomy (EPP), a radiation dose of 45.0 Gy in 25 fractions was given to cover 95% of the PTV. The lung V5s of the three patients were 14.3%, 10.0%, and 31.3%, respectively. The V5s of the present plans was smaller than that of the recent IMRT planning studies. The lung V20s of these patients were 2.4%, 2.2%, and 4.3%, respectively. Their MLDs were 4.3 Gy, 3.4 Gy, and 5.8 Gy, respectively. The follow-up periods of the patients were 26, 14 and 9 months from initiation of IMRT, respectively. All patients were alive, although local and contralateral recurrences had developed in 1 patient. Only 1 patient had Grade 2 acute esophagitis and nausea. There was no treatment-related pneumonitis. Hemithoracic IMRT using helical tomotherapy may play a crucial role in adjuvant treatment for MPM after EPP.

Extrapleural pneumonectomy, photodynamic therapy and intensity modulated radiation therapy for the treatment of malignant pleural mesothelioma

Intensity modulated radiation therapy (IMRT) has recently been proposed for the treatment of malignant pleural mesothelioma (MPM). Here, we describe our experience with a multimodality approach for the treatment of mesothelioma, incorporating extrapleural pneumonectomy, intraoperative photodynamic therapy and postoperative hemithoracic IMRT. From 2004-2007, we treated 11 MPM patients with hemithoracic IMRT, 7 of whom had undergone porfimer sodium-mediated PDT as an intraoperative adjuvant to surgical debulking. The median radiation dose to the planning treatment volume (PTV) ranged from 45.4-54.5Gy. For the contralateral lung, V20 ranged from 1.4 - 28.5%, V5 from 42 - 100%, and MLD from 6.8 - 16.5Gy. In our series, 1 patient experienced respiratory failure secondary to radiation pneumonitis that did not require mechanical ventilation. Multimodality therapy combining surgery with increased doses of radiation using IMRT, and newer treatment modalities such as PDT, appears safe. Future prospective analysis will be needed to demonstrate efficacy of this approach in the treatment of malignant mesothelioma. Efforts to reduce lung toxicity and improve dose delivery are needed and provide the promise of improved local control and quality of life in a carefully chosen multidisciplinary approach.