Radical Radiation Therapy After Lung-Sparing Surgery for Malignant Pleural Mesothelioma: Survival, Pattern of Failure, and Prognostic Factors.

PURPOSE: To prospectively assess the survival, patterns of failure, and prognostic factors in a large cohort of patients with malignant pleural mesothelioma who had undergone a novel trimodal therapeutic approach, including lung-sparing surgery, chemotherapy, and subsequent treatment with high doses of intensity modulated radiation therapy (IMRT) to the whole hemithorax. METHODS AND MATERIALS: The analysis was conducted on the data from 69 patients. Of the 69 patients, 35 underwent extended pleurectomy/decortication (P/D), with resection of the entire pleura, along with portions of the pericardium and diaphragm and 34, partial pleurectomy, defined as partial removal of parietal or visceral pleura for diagnostic purposes, leaving gross tumor behind in all cases. All patients received cisplatin/pemetrexed chemotherapy. Postoperative IMRT was delivered to the entire hemithorax, excluding the intact lung. The IMRT dose was 50 Gy in 25 fractions. Any fluorodeoxyglucose-avid areas or regions of particular concern for residual disease were given a simultaneous boost to 60 Gy. RESULTS: The median follow-up duration was 19 months. No difference was seen in overall survival and locoregional control between the extended P/D group and the partial pleurectomy group. The 2-year overall survival was 65% and 58% in the extended P/D and partial pleurectomy groups, respectively (P=.94). Locoregional control at 2 years was 65% and 64% in the extended P/D and partial pleurectomy groups, respectively (P=.75). The predominant pattern of failure was distant: 19 patients (27.5%) developed distant metastases as the first site of relapse. Gross residual disease after surgery was significantly associated with overall survival (hazard ratio 3.45). One fatal pneumonitis was reported; 14 cases (20%) of grade 2 to 3 pneumonitis were documented. CONCLUSIONS: Radical IMRT after lung-sparing surgery and chemotherapy for malignant pleural mesothelioma leads to promising survival results and acceptable toxicity rates. The similarity of survival between patients treated with extended P/D or partial pleurectomy observed in our study is intriguing.

Prognostic Score of Long-Term Survival After Surgery for Malignant Pleural Mesothelioma: A Multicenter Analysis.

BACKGROUND: Despite ongoing efforts to improve therapy in malignant pleural mesothelioma, few patients undergoing extrapleural pneumonectomy experience long-term survival (LTS). This study aims to explore predictors of LTS after extrapleural pneumonectomy and to define a prognostic score. METHODS: From January 2000 to December 2010, we retrospectively reviewed clinicopathologic and oncological factors in a multicenter cohort of 468 malignant pleural mesothelioma patients undergoing extrapleural pneumonectomy. LTS was defined as survival longer than 3 years. Associations were evaluated using χ(2), Student's t, and Mann-Whitney U tests. Logistic regression, Cox regression hazard model, and bootstrap analysis were applied to identify outcome predictors. Survival curves were calculated by the Kaplan-Meier method. Receiver operating characteristic analyses were used to estimate optimal cutoff and area under the curve for accuracy of the model. RESULTS: Overall, 107 patients (22.9%) survived at least 3 years. Median overall, cancer-specific, and disease-free survival times were 60 (95% confidence interval [CI], 51 to 69), 63 (95% CI, 54 to 72), and 49 months (95% CI, 39 to 58), respectively. At multivariate analysis, age (odds ratio, 0.51; 95% CI, 0.31 to 0.82), epithelioid histology (odds ratio, 7.07; 95% CI, 1.56 to 31.93), no history of asbestos exposure (odds ratio, 3.13; 95% CI, 1.13 to 8.66), and the ratio between metastatic and resected lymph nodes less than 22% (odds ratio, 4.12; 95% CI, 1.68 to 10.12) were independent predictors of LTS. According to these factors, we created a scoring system for LTS that allowed us to correctly predict overall, cancer-specific, and disease-free survival in the total sample, obtaining two different groups with favorable or poor prognosis (area under the curve, 0.74; standard error, 0.04; p < 0.0001). CONCLUSIONS: Our prognostic model facilitates the prediction of LTS after surgery for malignant pleural mesothelioma and can help to stratify the outcome and, eventually, tailor postoperative treatment.

Extrapleural pneumonectomy for malignant mesothelioma: an Italian multicenter retrospective study.

BACKGROUND: This study assessed perioperative outcome and long-term survival in a large series of patients with malignant pleural mesothelioma who underwent extrapleural pneumonectomy (EPP) to identify prognostic factors allowing better patient selection. METHODS: We retrospectively collected data from nine referral centers for thoracic surgery in Italy. Perioperative outcome and survival data were available for 518 malignant pleural mesothelioma patients (84.4% with epithelial tumors, 68.0% with pathologic stage 3 disease) who underwent EPP with intention-to-treat (R0/R1) between 2000 and 2010. Induction chemotherapy was administered in 271 patients (52.3%) and adjuvant therapy in 373 patients (72.0%), including radiotherapy in 213 patients (41.1%), adjuvant chemotherapy in 43 patients (8.3%), and both in 117 patients (22.6%). RESULTS: In all, 136 patients (26.3%) had major complications after EPP, and 36 (6.9%) died within 90 days after surgery. The median overall survival was 18 months, with a 1-, 2-, and 3-year overall survival of 65%, 41%, and 27%, respectively. At multivariable analysis adjusted for age and disease stage, male sex (hazard ratio [HR] 1.47, 95% confidence interval [CI]: 1.12 to 1.92), nonepithelial histology (HR 1.96, 95% CI: 1.48 to 2.58), and trimodality treatment using induction chemotherapy (HR 0.61, 95% CI: 0.43 to 0.85) were significantly associated with survival. Development of a major complication also significantly worsened outcome (HR 1.85, 95% CI: 1.37 to 2.50). CONCLUSIONS: The success of EPP in the context of a multimodality treatment depends on a series of patient characteristics. Female patients, patients with epithelial tumors, and patients who received induction chemotherapy will best benefit from EPP.

Radical pleurectomy/decortication followed by high dose of radiation therapy for malignant pleural mesothelioma. Final results with long-term follow-up.

PURPOSE: We have previously shown the feasibility of delivering high doses of radiotherapy in malignant pleural mesothelioma (MPM) patients who underwent radical pleurectomy/decortication (P/D) or surgical biopsy. In this report, we present the long-term results of MPM patients treated with radical P/D followed by high doses of radiotherapy. METHODS AND MATERIALS: Twenty consecutive MPM patients were enrolled in this prospective study and underwent radical P/D followed by high dose radiotherapy. The clinical target volume was defined as the entire hemithorax excluding the intact lung. The dose prescribed was 50 Gy in 25 fractions. Any FDG-avid areas or regions of particular concern for residual disease were given a simultaneous boost to 60 Gy. Nineteen patients received cisplatin/pemetrexed chemotherapy. Kaplan-Meier analysis was used to calculate rates of overall survival (OS), progression-free survival (PFS), and loco-regional control (LRC). RESULTS: The median follow-up was of 27 months. The median OS and PFS were 33 and 29 months, respectively. The median LRC was not reached. The Kaplan-Meier estimates of OS at 2 and 3 years were 70% and 49%, respectively. The estimates of PFS at 2 and 3 years were 65% and 46%, respectively. The estimates of LRC at 2 and 3 years were 68% and 59%, respectively. The predominant pattern of failure was distant: 7 patients developed distant metastases as the first site of relapse, whereas only 3 patients experienced an isolated loco-regional recurrence. No fatal toxicity was reported. Five Grades 2-3 pneumonitis were documented. CONCLUSIONS: High dose radiation therapy following radical P/D led to excellent loco-regional control and survival results in MPM patients. A median OS of 33 months and a 3-year OS rate of 49% are among the best observed in recent studies, supporting the idea that this approach represents a concrete therapeutic option for malignant pleural mesothelioma.

Tomotherapy after pleurectomy/decortication or biopsy for malignant pleural mesothelioma allows the delivery of high dose of radiation in patients with intact lung.

INTRODUCTION: This study aimed to assess the safety of high doses of radiation delivered with tomotherapy to the intact lung after radical pleurectomy/decortication or biopsy for malignant pleural mesothelioma (MPM). METHODS: Twenty-eight patients were enrolled in this prospective study and underwent adjuvant or definitive tomotherapy after radical pleurectomy/decortication (n = 20) or pleural biopsy (n = 8) for MPM. The dose prescribed to the planning target volume, defined as the entire hemithorax, including chest-wall incisions and drain sites and excluding the intact lung, was 50 Gy delivered in 25 fractions. All patients underwent fluorodeoxyglucose-positron emission tomography for staging after surgery. Any fluorodeoxyglucose-avid areas or regions of particular concern for residual disease were given a simultaneous boost of radiotherapy to 60 Gy. Specific lung dosimetric parameters were reported. Toxicity was graded using the modified Common Toxicity Criteria version 3.0. RESULTS: The median follow-up was of 19 months (range, 6-29 months). Five patients (17.8%) experienced severe respiratory symptoms corresponding to grade 2 pneumonitis in three cases, and grade 3 pneumonitis in two cases. No fatal respiratory toxicity was reported. Controlateral lung V5 was strongly correlated with the risk of pneumonitis. Patients who developed grade 2 and 3 pneumonitis had a higher controlateral lung V5 (mean V5=32%) than those without pneumonitis (mean V5=17%) (p=0.002). Other two grade 3 toxicities were registered: one severe pain to the chest wall, and one severe thrombocytopenia. CONCLUSIONS: Tomotherapy allows the safe delivery of high dose of radiation to the hemithorax of MPM patients with intact lung.

Real surgical morbidity and mortality after extrapleural pneumonectomy.

As for other major thoracic operations the conventional 30-day morbidity and mortality marker may underestimate the actual surgical risk of extrapleural pneumonectomy. We retrospectively analysed the prolonged follow-up of 78 patients submitted to extrapleural pneumonectomy for pleural mesothelioma (55), lung cancer with associated carcinomatous (7) or purulent (8) pleuritis, empyema/destroyed lung (4), and mediastinal (2) and chest wall (2) tumours with pleuro-pulmonary involvement. Significant rates of surgery-related major complications (19%) and fatalities (6.6%) additionally occurred beyond 30 days and within 6 months of extrapleural pneumonectomy, making a 66% cumulative (early + late) morbidity rate and an 11.5% cumulative mortality rate, which are respectively 50% and 100% greater than the 30-day rate alone. The leading causes of late morbidity and mortality were respiratory/cardiac sequelae (50%) and broncho-pleural fistulas (30%). Strict preoperative functional selection and proper application of the technical learning curve can reduce the occurrence of the adverse events by anything up to 50% (early mortality: 2.3%). If the results of this novel study of long-term surgical outcomes of extrapleural pneumonectomy were to be confirmed, the preoperative risk/benefit balance of the procedure, mainly when performed for thoracic malignancies, should therefore include the entire spectrum of (early and late) potential surgery-related complications.

Intraoperative identification and effective "blood patch" prevention of persistent air leak in lung resections.

Persistent air leak (PAL) is the most common complication after lung resection, requiring additional treatments and hospital stay. Intraoperative prevention of PAL is usually left to the surgeon's subjective judgement, with inconsistent results. The aim of the study was to establish systematic, reproducible quantification of air leaks at thoracotomy in order to identify those which are potentially persistent, to be preventively treated by intraoperative "blood patch" pneumo-stasis. In a consecutive series of 570 lung resections, parenchymal suture air tightness was tested intraoperatively at end-inspiratory pressure intervals from 15 to 35 cm H2O. Air leaks at 15 cm H2O (n=40) were considered too critical, while air escape beyond 30 cm H2O (n=437) was deemed quickly self-sealing postoperatively; these conditions were managed by further surgery and standard chest tubes only, respectively. Air leaks between 16 and 30 cm H20 (n=93) were assumed to be the main source of postoperative PAL and were preventively treated with 50 cc of blood left in the cavity for 3 hours after closing the thoracotomy. Chest tubes were set up so as to avoid tension pneumothorax or occult bleeding. No early or late major complications were related to the intraoperative "blood patch" procedure. The cumulative incidence of PAL was 1.4%, most of which (6/8) belonging to the group leaking air in the 16-30 cm H2O pressure interval. In contrast, the PAL rate in the 437 patients reputed to be at low risk was 0.2%. The overall mean hospital stay was 7.2 days, the mean duration of chest tube duration 3.5 days, and the complication rate 15%. According to our retrospective data, air leaks occurring between 16 and 30 cm H2O of pressure in the intubated lung were identified as carrying the highest risk of becoming persistent postoperatively; intraoperative "blood patch" pneumo-stasis is a convenient and successful preventive method to minimize PAL occurrence in this group of patients.

Surgical outcome of lung cancer patients with carcinomatous pleuritis.

In sporadic though non-anecdotal series, long-term survival has been reported for patients operated on for lung cancer with secondary carcinomatous pleuritis. In a retrospective study, we review the outcomes of 24 surgical patients (20 treated with standard lung resection +/- pleurectomy and 4 with extended pleuropneumonectomy) out of 48 individuals affected by pleural spread before or at thoracotomy. We observed a 16.6% major complication rate with no operative mortality; 5-year and median survival were 20% and 21 months, respectively. Time of diagnostic (pre- vs intra/postoperative) or pattern (effusion vs dissemination) of pleural disease, and type of resection (standard vs extended) did not seem to influence the prognosis, while an adenocarcinoma histotype, completeness of excision and N(0-1) were favourable prognostic indicators. Since most (90%) of these IIIB stages are usually associated with N(2-3) and/or unresectable tumour, it would seem reasonable to employ neo-adjuvant treatment as the first approach, reserving surgical treatment to responders. Multicentre studies are necessary to better determine which subgroup of patients with malignant pleuritis can most benefit from surgical therapy.

[Thoracic outlet syndrome: clinical staging]. / Sindrome dello stretto toracico superiore: stadiazione clinica.

The clinical and instrumental manifestations of thoracic outlet syndrome are well known but the therapeutic choices frequently differ in relation to the physician's experience. Thus, there is no univocal opinion regarding the therapy of this complex syndrome. To solve this problem we have attempted to bring together the clinical and instrumental pictures in a single classification that includes the three fundamental aspects of the syndrome, namely nerve, artery and vein injury (NAV). Our goal was to achieve a universally accepted therapy-oriented staging system, as is the case with the TNM system for malignant tumours. From 1984 to 2002, in our institution 156 patients with thoracic outlet syndrome were evaluated. These were grouped in 4 stages depending on their NAV status. Subsequent therapy was in accordance with stage. Our results confirmed the accuracy of NAV. On the basis of our preliminary experience, the NAV staging system is useful for correct patient grouping. Now a prospective multicentre study is needed for universal scientific validation.

[Pleuro-pneumonectomy, RT and CT for pleural mesothelioma. Prospective study]. / Pleuro-pneumonectomia, RT e CT per mesotelioma pleurico. Uno studio prospettico.

Though associated with substantially prolonged survival, the favourable results of Sugarbaker's trimodality treatment for malignant pleural mesothelioma are controversial and have yet to be extensively reproduced. The aim was to evaluate the prospective medium-term (3-year) reproducibility of the results of trimodality treatment in a significant group of patients staged using the international IMIG classification. Forty-three patients with malignant pleural mesothelioma were candidates for extended pleuropneumonectomy, followed by chemo- and radiotherapy. At thoracotomy, 33 of the 43 surgical candidates underwent extended pleuropneumonectomy and 71% of the 30 evaluable operated patients completed the scheduled course of adjuvant chemotherapy. The perioperative mortality rate was 6% and the major morbidity rate 36%. At 3 years the overall survival of the 30 evaluable patients was 30% and the disease-free survival rate was 25%, with a prevalence of epithelial pI and pII IMIG stages. Clinical understaging was appreciable. Survival was less favourable for stage pIII and for mixed tumours. Most of the disease recurrences were due to incomplete local postsurgical monitoring. This series confirms the reproducibility of trimodality treatment for malignant pleural mesothelioma. The treatment is associated with prolonged survival in the case of early-stage tumours and has an acceptable complication rate. Early diagnosis, accurate staging, preoperative induction and better local monitoring are avenues to be explored when seeking to achieve curability of malignant pleural mesothelioma.