Genomic profiling of tissue and blood predicts survival outcomes in patients with resected pleural mesothelioma.

PURPOSE: Pleural mesothelioma (PM) is an aggressive tumor still considered incurable, in part due to the lack of predictive biomarkers. Little is known about the clinical implications of molecular alterations in resectable PM tissues and blood. Here, we characterized genetic alterations to identify prognostic and predictive biomarkers in patients with resected PM. EXPERIMENTAL DESIGN: Targeted next-generation sequencing was performed in retrospective pleural tumor tissue and paired plasma samples from stage IB-IIIB resected PM. Association between prognosis and presence of specific mutations was validated in silico. RESULTS: Thirty PM tissues and paired blood samples from 12 patients were analyzed. High tissue tumor mutational burden (TMB) (>10 mutations/Mb), tissue median minor allele frequency (MAF) (>9 mutations/Mb), and blood TMB (>6 mutations/Mb), tissue KMT2C, PBRM1, PKHD1,EPHB1 and blood LIFR mutations correlated with longer disease-free survival and/or overall survival. High concordance (>80%) between tissue and blood was found for some mutations. CONCLUSIONS: Tissue TMB and MAF, blood TMB, and specific mutations correlated with outcomes in patients with resected PM and should be further studied to validate their role as prognostic biomarkers and potentially predictive factors for combinations with immune-checkpoint inhibitors. This suggest that molecular profiling could identify longer survivors in patients with resected PM.

Laying the Foundation for a Mesothelioma Patient Registry: Development of Data Collection Tools.

Mesothelioma, a cancer of mesothelial cells that line the chest, lungs, heart, and abdomen, is a relatively rare disease. In the United States, approximately 3000 individuals are diagnosed with mesothelioma annually. The primary risk factor for mesothelioma is occupational asbestos exposure which can occur decades prior to disease development, though in approximately 20% of cases, known asbestos exposure is lacking. While several other countries have developed mesothelioma registries to collect key clinical and exposure data elements to allow better estimation of incidence, prevalence, and risk factors associated with disease development, no national mesothelioma registry exists in the U.S. Therefore, as part of a larger feasibility study, a patient exposure questionnaire and a clinical data collection tool were created using a series of key informant interviews. Findings suggest that risk factor and clinical data collection via an on-line questionnaire is feasible, but specific concerns related to confidentiality, in the context of employer responsibility for exposure in the unique U.S. legal environment, and timing of enrollment must be addressed. Lessons learned from piloting these tools will inform the design and implementation of a mesothelioma registry of national scope.

Examining the impact of physical function performance in predicting patient outcomes after lung-sparing surgery for malignant pleural mesothelioma.

PURPOSE: The purpose of this study was to examine the impact of physical function performance and pulmonary function on patient outcomes after lung-sparing surgery for malignant pleural mesothelioma (MPM). MATERIALS AND METHODS: A retrospective review of 54 patients with MPM from 2015 to 2020 was performed. The primary objective was to assess whether physical function, as measured by the Eastern Cooperative Oncology Group Performance Status (ECOG), and pulmonary function tests were predictive of postoperative patient outcomes (ventilator days, chest tube days, hospital length of stay). A secondary objective was to explore demographic and preoperative variables that best predict postoperative physical function and patient outcomes. RESULTS: Data include 54 patients who underwent extended pleurectomy-decortication. Preoperative ECOG was a significant predictor of postoperative patient outcomes while preoperative lung function lacked predictive ability. Preoperative ECOG was also predictive of preoperative lung function. Age on the day of surgery was the best predictor of postoperative physical function, which was significantly reduced postoperatively. CONCLUSIONS: Preoperative physical function performance was a significant predictor of postoperative outcomes. The results of our study highlight the importance of physical function in patients with MPM and support the need for early rehabilitation and further research to determine optimal rehabilitation interventions.IMPLICATIONS FOR REHABILITATIONPreoperative physical function can predict outcomes after lung-sparing surgery for malignant pleural mesothelioma (MPM).Physical function in patients with MPM should be carefully examined.To accurately reflect patients' abilities, patient assessment should include both patient-reported outcomes and performance-based measures.Patients with MPM should receive rehabilitation early after diagnosis and throughout the continuum of care.

CT for detection of malignant posterior intercostal lymph nodes in patients undergoing pre-operative staging for malignant pleural mesothelioma.

INTRODUCTION: Recent evidence suggests that patients with malignant pleural mesothelioma (MPM) undergoing extended pleurectomy/decortication (eP/D) with metastasis to the posterior intercostal lymph nodes (PILN) have a worse prognosis. In this study, we determine if MPM PILN metastasis can be reliably detected on computed tomography (CT). MATERIALS AND METHODS: Preoperative staging CT exams were reviewed for the presence of PILN in MPM patients undergoing eP/D between 2007-2013 with surgical sampling of their PILN. CT images were reviewed by two thoracic radiologists blinded to clinical records, including operative pathology reports. The number and short axis size of PILN were recorded and correlated with surgical pathology. Statistical analysis examined the value of preoperative CT to detect metastatic PILN. RESULTS: Of 36 patients that underwent eP/D with PILN sampling had preoperative CT images for review. At surgery, 22 of these patients had metastatic PILN and 14 had benign PILN. The positive and negative predictive values for one or more nodes seen on preoperative CT were 60 % and 38 % respectively. The number of PILN on preoperative CT did not predict metastasis (p = 0.40) with an average of 2 PILN seen, regardless of PILN pathology. The average nodal short axis size was 4.6 mm and 4.8 mm for benign and malignant PILN, respectively, and PILN short axis size did not predict metastasis (p = 0.39). There was little inter-observer variability between the size and number of nodes detected by each radiologist. CONCLUSIONS: CT does not reliably identify metastatic PILN on preoperative CT for patients with MPM undergoing extended pleurectomy/decortication.

Nursing and Allied Health Research Priorities in the Care of Patients With Thoracic Malignancies: An International Cross-Sectional Survey.

BACKGROUND: There is currently no evidence of research priorities from nurses and allied health professionals working in the field of thoracic malignancies, which could provide strategic directions for funders, policy makers, and researchers. OBJECTIVE: The aim of this study is to identify the priorities for lung cancer and other thoracic malignancies research and practice in nurses and allied health professionals. METHODS: Descriptive cross-sectional web-based international survey conducted through international societies' membership lists. RESULTS: Participants included 152 nurses and allied health professionals. Key priority categories were related to developing and evaluation interventions; symptom management interventions; health care system issues; treatment-related research (immunotherapy; targeted therapies); persistent/late effects management (fatigue; pulmonary toxicity); risk reduction, and screening research. The specific topic with the highest endorsement (80.9%) was the development of interventions to improve quality of life. Symptom management interventions, particularly for pain, dyspnea, and fatigue, were also highly endorsed. Health care system topics were related to delivery of care and included nurse-/allied health-led care (67.5%), working with the multidisciplinary team (67.5%), continuity of care (69.2%), and access to care (67.5%). Topics around screening/early detection research were highly endorsed too. CONCLUSION: A clear focus (and need) for research in interventions to improve quality of life and symptom management, particularly for pain, dyspnea, and fatigue was also established, alongside healthcare system issues and screening research. IMPLICATIONS FOR PRACTICE: International societies and funding bodies could consider these topics in their funding decisions and in shaping their strategic directions in the care of patients with thoracic malignancies.

Posterior Intercostal Lymph Nodes Double Recurrence and Death Risk in Malignant Pleural Mesothelioma.

BACKGROUND: Posterior intercostal lymph nodes, previously undescribed for cancer staging, are part of the lymphatic drainage of the pleural space. This study assessed the impact of posterior intercostal lymph nodes on survival in patients undergoing extended pleurectomy/decortication for malignant pleural mesothelioma. METHODS: As part of the thoracic lymphadenectomy, posterior intercostal lymph nodes were accessed by incising the endothoracic fascia at the level of the rib heads. These nodes were systematically harvested in 56 consecutive patients undergoing extended pleurectomy decortication in a clinical trial. The impact of these nodes on progression-free (PFS) and overall survival (OS) was analyzed by multiple statistical methods. RESULTS: Median PFS and OS were 11.6 and 25.5 months, respectively. In 6 of 56 patients (11%), posterior intercostal lymph nodes were the only positive nodes, and overall, 48.2% had posterior intercostal lymph node metastases. Patients with N2 disease had significantly poorer prognosis if the posterior intercostal lymph nodes were involved: PFS (7.3 vs 14.9 months, P = .002) and OS (14.4 vs 26.1 months, P = .028). In the multivariable models, after adjustment for nodal stage and other prognostic factors, intercostal nodes remained associated with a 2.5-fold elevated risk of progression (P < .001) and a 2.3-fold elevated risk of death (P < .001). CONCLUSIONS: Metastases to posterior intercostal lymph nodes independently more than doubled the risk of progression and death and were the only site of nodal metastases in 11% of patients. These nodes warrant further investigation, including nonoperative techniques to identify and factor them into treatment decision making.

Lymphangitic carcinomatosis: A common radiographic manifestation of local failure following extended pleurectomy/decortication in patients with malignant pleural mesothelioma.

INTRODUCTION: The lymphangitic carcinomatosis (LC) pattern of metastatic malignancy is associated with a poor prognosis but is currently not well defined in malignant pleural mesothelioma (MPM). Here, we report the incidence and prognostic significance of the radiographic development of LC in MPM following extended pleurectomy/decortication (EPD). METHODS: Consecutive patients with biopsy-proven MPM undergoing EPD with intraoperative photodynamic therapy (PDT) at our institution from 2008 to 2014 were included in this retrospective study. Patients without available post-surgical clinical or imaging data for direct review were excluded. CT images were reviewed by an experienced, board-certified thoracic radiologist and confirmed by consensus review. Overall survival (OS) and progression-free survival (PFS) were calculated by Kaplan Meier methodology. Hazard ratios were compared with a cox proportional hazard model. RESULTS: 44 patients underwent EPD with PDT during the study period and had available clinical and imaging data. During the follow-up period (median 34 months), 17 patients (39%) developed LC at a median of 10 months after surgery (IQR 5-21 months). 16 of the 17 patients who developed LC (94%) died during the follow-up period, compared to 17 of the 27 who did not develop LC (63%). OS for the LC versus non-LC group was 53% versus 93% at 1 year and 18% versus 67% at 3 years. LC was significantly associated with a lower OS (HR 4.07; 95% confidence interval 1.44-11.48; p = 0.008). PFS for the LC group versus non-LC group was 8 months (IQR 5-9 months) compared to 17 months (IQR 11-24 months) (p < 0.001). CONCLUSION: LC is a common form of failure in MPM following EPD and is associated with a poor prognosis. Thus, further studies are warranted to determine if any evidence of preoperative LC should be an absolute contraindication to EPD and may warrant an EPP or no surgery at all.

A Proposed System Toward Standardizing Surgical-Based Treatments for Malignant Pleural Mesothelioma, From the Joint National Cancer Institute-International Association for the Study of Lung Cancer-Mesothelioma Applied Research Foundation Taskforce.

This article is a joint effort arising from a task force formed at a National Cancer Institute-International Association for the Study of Lung Cancer-Mesothelioma Applied Research Foundation Mesothelioma Clinical Trials Planning Meeting, held at the NIH in March 2017. Malignant pleural mesothelioma remains one of the most virulent and recalcitrant malignancies, still considered incurable, and in desperate need of clinical trials in order to make progress for our patients. Although not standard of care, there is compelling evidence that a select subgroup of mesothelioma patients benefit from a surgery-based multimodal approach. As it is not possible to achieve a microscopically complete resection with mesothelioma, there appears to be no role for surgery alone. Thus, it is anticipated that significant strides in the surgery-based treatment of this cancer will require trials that determine which complementary treatments best augment the cytoreductive efficacy of surgery. Although lung-sacrificing surgery for mesothelioma is fairly standardized, approaches to lung-sparing surgery are highly variable and lung sparing surgery is emerging internationally as the dominant extirpative procedure for this cancer. It is not currently possible to rigorously assess the contribution of the adjuvant treatments combined with surgery because of the variability in procedures used to debulk this cancer, the extreme variability of the cancer itself, the variability in patient selection, the variability in treatment of the inevitable recurrence, and even the variability in follow up schedules. This article is an effort to address these problems by suggesting a more uniform approach to the surgical procedure and also proposing a series of data collection forms that could be adopted immediately, with any eye toward collecting the information that will be necessary to facilitate patient selection and determine which aspects of mesothelioma surgery can and should be standardized - with the goal being extension of life while maintaining quality of life as an equal priority. Furthermore, a completely original contribution in this manuscript is the proposal of a grading system that takes the information from the surgical procedure data forms and generates a completeness of resection score. This is the initial effort to establish a common denominator for mesothelioma surgery that will allow for more accurate comparison between surgical series and better assessment of the impact of the treatments combined with surgery.

Survival by Histologic Subtype of Malignant Pleural Mesothelioma and the Impact of Surgical Resection on Overall Survival.

INTRODUCTION: For the 3 histologic subtypes of malignant pleural mesothelioma (MPM)-epithelioid, sarcomatoid, and biphasic-the magnitude of benefit with surgical management remains underdefined. MATERIALS AND METHODS: The National Cancer Data Base was queried for newly diagnosed nonmetastatic MPM with known histology. Patients in each histologic group were dichotomized into those receiving gross macroscopic resection versus lack thereof/no surgery. Kaplan-Meier analysis evaluated overall survival (OS) between cohorts; multivariable Cox proportional hazards modeling assessed factors associated with OS. After propensity matching, survival was evaluated for each histologic subtype with and without surgery. RESULTS: Overall, 4207 patients (68% epithelioid, 18% sarcomatoid, 13% biphasic) met the study criteria. Before propensity matching, patients with epithelioid disease experienced the highest median OS (14.4 months), followed by biphasic (9.5 months) and sarcomatoid (5.3 months) disease; this also persisted after propensity matching (P < .001). After propensity matching, surgery was associated with significantly improved OS for epithelioid (20.9 vs. 14.7 months, P < .001) and biphasic (14.5 vs. 8.8 months, P = .013) but not sarcomatoid (11.2 vs. 6.5 months, P = .140) disease. On multivariable analysis, factors predictive of poorer OS included advanced age, male gender, uninsured status, urban residence, treatment at community centers, and T4/N2 disease (all P < .05). Chemotherapy and surgery were independently associated with improved OS, as was histology (all P < .001). CONCLUSION: This large investigation evaluated surgical practice patterns and survival by histology for MPM and found that histology independently affects survival. Gross macroscopic resection is associated with significantly increased survival in epithelioid and biphasic, but not sarcomatoid, disease. However, the decision to perform surgery should continue to be individualized in light of available randomized data.

A preclinical model to investigate the role of surgically-induced inflammation in tumor responses to intraoperative photodynamic therapy.

OBJECTIVE: Inflammation is a well-known consequence of surgery. Although surgical debulking of tumor is beneficial to patients, the onset of inflammation in injured tissue may impede the success of adjuvant therapies. One marker for postoperative inflammation is IL-6, which is released as a consequence of surgical injuries. IL-6 is predictive of response to many cancer therapies, and it is linked to various molecular and cellular resistance mechanisms. The purpose of this study was to establish a murine model by which therapeutic responses to photodynamic therapy (PDT) can be studied in the context of surgical inflammation. MATERIALS AND METHODS: Murine models with AB12 mesothelioma tumors were treated with either surgical resection or sham surgery with tumor incision but no resection. The timing and extent of IL-6 release in the tumor and/or serum was measured using enzyme-linked immunosorbent assay (ELISA) and compared to that measured in the serum of 27 consecutive, prospectively enrolled patients with malignant pleural mesothelioma (MPM) who underwent macroscopic complete resection (MCR). RESULTS: MPM patients showed a significant increase in IL-6 at the time MCR was completed. Similarly, IL-6 increased in the tumor and serum of mice treated with surgical resections. However, investigations that combine resection with another therapy make it necessary to grow tumors for resection to a larger volume than those that receive secondary therapy alone. As the larger size may alter tumor biology independent of the effects of surgical injury, we assessed the tumor incision model. In this model, tumor levels of IL-6 significantly increased after tumor incision. CONCLUSION: The tumor incision model induces IL-6 release as is seen in the surgical setting, yet it avoids the limitations of surgical resection models. Potential mechanisms by which surgical induction of inflammation and IL-6 could alter the nature and efficacy of tumor response to PDT are reviewed. These include a wide spectrum of molecular and cellular mechanisms through which surgically-induced IL-6 could change the effectiveness of therapies that are combined with surgery. The tumor incision model can be employed for novel investigations of the effects of surgically-induced, acute inflammation on therapeutic response to PDT (or potentially other therapies). Lasers Surg. Med. 50:440-450, 2018. © 2018 Wiley Periodicals, Inc.

Facility volume and postoperative outcomes for malignant pleural mesothelioma: A National Cancer Data Base analysis.

PURPOSE: This study of a large, contemporary national database evaluated postoperative outcomes and overall survival (OS) for malignant pleural mesothelioma (MPM) by facility volume. METHODS: The National Cancer Database was queried for newly-diagnosed non-metastatic MPM undergoing definitive surgery (extrapleural pneumonectomy (EPP) or pleurectomy/decortication (P/D)). Patients were dichotomized into those receiving therapy at a high-volume facility (HVF), defined a priori at the 90th percentile of case volume, with all others categorized as lower-volume facilities (LVFs). Statistics included multivariable logistic regression, Kaplan-Meier analysis, propensity-matching, and multivariable Cox proportional hazards modeling. Sensitivity analysis varied the dichotomized HVF-LVF cutoff and evaluated effects on postoperative outcomes and OS. RESULTS: Of 1307 patients, 621 (48%) were treated at LVFs and 686 (52%) at HVFs. HVFs were more often in the Middle/South Atlantic regions, and less likely in New England, South, and Midwest. Notably, 75% of procedures at HVFs were P/Ds, versus 84% at LVFs (p < 0.001). Patients treated at HVFs experienced shorter length of postoperative hospitalization (p = 0.035), lower 30-day readmission rates (4.6% vs. 6.1%, p = 0.021), and lower 90-day mortality rates (10.0% vs. 14.6%, p = 0.029). Median OS for respective groups were 18 versus 15 months (p = 0.010), which were not significant following propensity-matching (p = 0.540). On multivariable analysis, facility volume did not independently predict for OS. Sensitivity analyses confirmed the postoperative outcomes and OS findings. CONCLUSIONS: This is the largest investigation to date assessing facility volume and outcomes following surgery for MPM. Although no independent effects on OS were observed, postoperative outcomes were more favorable at HVFs. These findings have implications for postoperative management, patient counseling, referring providers, and cost-effectiveness.

National Cancer Database Report on Pneumonectomy Versus Lung-Sparing Surgery for Malignant Pleural Mesothelioma.

INTRODUCTION: Controversy exists regarding the optimal surgical technique for malignant pleural mesothelioma (MPM). We evaluated national practice patterns and outcomes of MPM treated with extrapleural pneumonectomy (EPP) versus lung-sparing extended pleurectomy/decortication (P/D). METHODS: The National Cancer Database was queried for patients with newly diagnosed MPM undergoing EPP or P/D. Multivariable logistic regression ascertained clinical factors independently associated with P/D receipt. Kaplan-Meier analysis was used to evaluate overall survival (OS) between cohorts; multivariable Cox proportional hazards modeling was used to evaluate factors associated with OS. Survival was then evaluated between propensity-matched populations. RESULTS: Overall, 1307 patients (271 undergoing EPP [21%] and 1036 undergoing P/D [79%]) met the criteria. Patients receiving P/D were older (p = 0.028), whereas those undergoing EPP were more likely to live in a rural area (p = 0.044), live farther from the treating facility (p = 0.039), and receive treatment at an academic center (p = 0.050). There were no differences between cohorts in 30-day readmission or mortality (all p > 0.05). The median OS times in the EPP and P/D groups were 19 versus 16 months, respectively (p = 0.120); no differences were observed after propensity matching (p = 0.540). CONCLUSIONS: In this largest analysis of its kind to date, findings from this contemporary cohort demonstrate that P/D comprised most surgical procedures for MPM. Procedure type was influenced by sociodemographic and geographical factors, without observed differences in survival or postoperative mortality and readmission rates between techniques.

Immunotherapy and radiation therapy for operable early stage and locally advanced non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the most common cause of cancer mortality. Although a significant proportion of patients can be cured with surgery, with or without adjuvant or neoadjuvant chemotherapy and radiation, a significant proportion of patients will fail, particularly distantly. Over fifty percent of patients present with stage IV disease. There are multiple forms of immunotherapy available including T-cell transfer, cytokine therapy, and oncolytic viruses. Checkpoint inhibitors have shown tremendous activity in NSCLC and are currently under intense study given promising data on response. Immunotherapy and radiation therapy (RT) both show significant immune editing activity in NSCLC that may allow the innate and adaptive immune system to help control systemic disease by both radiosensitization and a sustained systemic immune response. Multiple clinical trials are underway exploring the role of adjuvant or neoadjuvant immunotherapy in operable NSCLC. A substantial amount of progress is to be made in terms of optimizing radiation dose and fractionation, immunotherapy type and dose, and integrating both to best realize the benefits of immunotherapy and radiation in operable lung cancer.

Extended Pleurectomy-Decortication-Based Treatment for Advanced Stage Epithelial Mesothelioma Yielding a Median Survival of Nearly Three Years.

BACKGROUND: The purpose of this study was to assess survival for patients with malignant pleural mesothelioma (MPM), epithelial subtype, utilizing extended pleurectomy-decortication combined with intraoperative photodynamic therapy (PDT) and adjuvant pemetrexed-based chemotherapy. METHODS: From 2005 to 2013, 90 patients underwent lung-sparing surgery and PDT for MPM. All patients had a preoperative diagnosis of epithelial subtype, of which 17 proved to be of mixed histology. The remaining 73 patients with pure epithelial subtype were analyzed. All patients received lung-sparing surgery and PDT; 92% also received chemotherapy. The median follow-up was 5.3 years for living patients. RESULTS: Macroscopic complete resection was achieved in all 73 patients. Thirty-day mortality was 3% and 90-day mortality was 4%. For all 73 patients (89% American Joint Commission on Cancer stage III/IV, 69% N2 disease, median tumor volume 550 mL), the median overall and disease-free survivals were 3 years and 1.2 years, respectively. For the 19 patients without lymph node metastases (74% stage III/IV, median tumor volume 325 mL), the median overall and disease-free survivals were 7.3 years and 2.3 years, respectively. CONCLUSIONS: This is a mature dataset for MPM that demonstrates the ability to safely execute a complex treatment plan that included a surgical technique that consistently permitted achieving a macroscopic complete resection while preserving the lung. The role for lung-sparing surgery is unclear but this series demonstrates that it is an option, even for advanced cases. The overall survival of 7.3 years for the node negative subset of patients, still of advanced stage, is encouraging. Of particular interest is the overall survival being approximately triple the disease-free survival, perhaps PDT related. The impact of PDT is unclear, but it is hoped that it will be established by an ongoing randomized trial.

Pilot and Feasibility Trial Evaluating Immuno-Gene Therapy of Malignant Mesothelioma Using Intrapleural Delivery of Adenovirus-IFNα Combined with Chemotherapy.

PURPOSE: "In situ vaccination" using immunogene therapy has the ability to induce polyclonal antitumor responses directed by the patient's immune system. EXPERIMENTAL DESIGN: Patients with unresectable malignant pleural mesothelioma (MPM) received two intrapleural doses of a replication-defective adenoviral vector containing the human IFNα2b gene (Ad.IFN) concomitant with a 14-day course of celecoxib followed by chemotherapy. Primary outcomes were safety, toxicity, and objective response rate; secondary outcomes included progression-free and overall survival. Biocorrelates on blood and tumor were measured. RESULTS: Forty subjects were treated: 18 received first-line pemetrexed-based chemotherapy, 22 received second-line chemotherapy with pemetrexed (n = 7) or gemcitabine (n = 15). Treatment was generally well tolerated. The overall response rate was 25%, and the disease control rate was 88%. Median overall survival (MOS) for all patients with epithelial histology was 21 months versus 7 months for patients with nonepithelial histology. MOS in the first-line cohort was 12.5 months, whereas MOS for the second-line cohort was 21.5 months, with 32% of patients alive at 2 years. No biologic parameters were found to correlate with response, including numbers of activated blood T cells or NK cells, regulatory T cells in blood, peak levels of IFNα in blood or pleural fluid, induction of antitumor antibodies, nor an immune-gene signature in pretreatment biopsies. CONCLUSIONS: The combination of intrapleural Ad.IFN, celecoxib, and chemotherapy proved safe in patients with MPM. OS rate was significantly higher than historical controls in the second-line group. Results of this study support proceeding with a multicenter randomized clinical trial of chemo-immunogene therapy versus standard chemotherapy alone. Clin Cancer Res; 22(15); 3791-800. ©2016 AACR.

Radical pleurectomy and intraoperative photodynamic therapy for malignant pleural mesothelioma.

BACKGROUND: Radical pleurectomy (RP) for mesothelioma is often considered either technically unfeasible or an operation limited to patients who would not tolerate a pneumonectomy. The purpose of this study was to review our experience using RP and intraoperative photodynamic therapy (PDT) for mesothelioma. METHODS: Thirty-eight patients (42-81 years) underwent RP-PDT. Thirty five of 38 (92%) patients also received systemic therapy. Standard statistical techniques were used for analysis. RESULTS: Thirty seven of 38 (97%) patients had stage III/IV cancer (according to the American Joint Committee on Cancer [AJCC manual 7th Edition, 2010]) and 7/38 (18%) patients had nonepithelial subtypes. Macroscopic complete resection was achieved in 37/38 (97%) patients. There was 1 postoperative mortality (stroke). At a median follow-up of 34.4 months, the median survival was 31.7 months for all 38 patients, 41.2 months for the 31/38 (82%) patients with epithelial subtypes, and 6.8 months for the 7/38 (18%) patients with nonepithelial subtypes. Median progression-free survival (PFS) was 9.6, 15.1, and 4.8 months, respectively. The median survival and PFS for the 20/31 (64%) patients with N2 epithelial disease were 31.7 and 15.1 months, respectively. CONCLUSIONS: It was possible to achieve a macroscopic complete resection using lung-sparing surgery in 97% of these patients with stage III/IV disease. The survival we observed with this approach was unusually long for the patients with the epithelial subtype but, interestingly, the PFS was not. The reason for this prolonged survival despite recurrence is not clear but is potentially related to preservation of the lung or some PDT-induced effect, or both. We conclude that the results of this lung-sparing approach are safe, encouraging, and warrant further investigation.

A trial of intrapleural adenoviral-mediated Interferon-α2b gene transfer for malignant pleural mesothelioma.

New therapeutic strategies are needed for malignant pleural mesothelioma (MPM). We conducted a single-center, open-label, nonrandomized, pilot and feasibility trial using two intrapleural doses of an adenoviral vector encoding human IFN-α (Ad.IFN-α2b). Nine subjects were enrolled at two dose levels. The first three subjects had very high pleural and systemic IFN-α concentrations resulting in severe "flu-like" symptoms necessitating dose de-escalation. The next six patients had reduced (but still significant) pleural and serum IFN-α levels, but with tolerable symptoms. Repeated vector administration appeared to prolong IFN-α expression levels. Anti-tumor humoral immune responses against mesothelioma cell lines were seen in seven of the eight subjects evaluated. No clinical responses were seen in the four subjects with advanced disease. However, evidence of disease stability or tumor regression was seen in the remaining five patients, including one dramatic example of partial tumor regression at sites not in contiguity with vector infusion. These data show that Ad.IFN-α2b has potential therapeutic benefit in MPM and that it generates anti-tumor immune responses that may induce anatomic and/or metabolic reductions in distant tumor. Clinical trial registered with www.clinicaltrials.gov (NCT 01212367).

Photodynamic therapy and the evolution of a lung-sparing surgical treatment for mesothelioma.

BACKGROUND: Photodynamic therapy (PDT) is a light-based cancer treatment that acts to a depth of several millimeters into tissue. This study reviewed the results of patients who underwent a macroscopic complete resection, by two different surgical techniques, and intraoperative PDT as a treatment for malignant pleural mesothelioma. METHODS: From 2004 to 2008, 28 patients with malignant pleural mesothelioma underwent macroscopic complete resection, 14 by modified extrapleural pneumonectomy (MEPP) and 14 by radical pleurectomy (RP) and intraoperative PDT. The surgical technique evolved over this period such that 13 of the last 16 patients underwent lung-sparing procedures, even in the setting of large-bulk tumors. RESULTS: Demographics in the MEPP and RP cohorts were similar in age, sex, stage, nodal status, histology, and adjuvant treatments. Stage III/IV disease was present in 12 of 14 patients (86%), with 50% or more with +N2 disease. The median overall survival for the MEPP group was 8.4 months, but has not yet been reached for the RP group at a median follow-up of 2.1 years. CONCLUSIONS: In addition to the inherent advantages of sparing the lung, RP plus PDT yielded a superior overall survival than MEPP plus PDT in this series. The overall survival for the RP plus PDT group was, for unclear reasons, superior to results reported in many surgical series, especially for a cohort with such advanced disease. Given these results, we believe RP plus PDT is a reasonable option for appropriate patients pursuing a surgical treatment for malignant pleural mesothelioma and that this procedure can serve as the backbone of surgically based multimodal treatments.

Phase II trial of pleural photodynamic therapy and surgery for patients with non-small-cell lung cancer with pleural spread.

PURPOSE: Non-small-cell lung cancer (NSCLC) with pleural spread is incurable, with median survival rates ranging from 6 to 9 months. Surgery alone fails to locally control this disease or extend survival beyond the accepted treatment, palliative chemotherapy. METHODS: We conducted a phase II trial to evaluate the effects on local control and survival of combining surgery with intraoperative photodynamic therapy (PDT), a light-based cancer treatment, in patients with NSCLC with pleural spread. Patients received porfimer sodium (2 mg/kg), 24 hours before surgery, at which time all gross tumor was resected and followed by illumination of the hemithorax with 630 nm light to a measured dose of 30 J/cm(2). Photosensitizer levels in tumor and surrounding normal tissue were measured. RESULTS: Twenty-two patients with NSCLC were enrolled; 17 underwent complete debulking and PDT, three underwent partial debulking/PDT, and two patients were unresectable. Local control of pleural disease at 6 months was achieved in 11 of 15 (73.3%; 95% CI, 44.9% to 92.2%) assessable patients. Median overall survival for all 22 patients was 21.7 months (95% CI, 17.7 to 25.8 months). Measured levels of porfimer sodium in tumor were greater than those measured in normal tissues, with ratios ranging from 1.19 to 22.42. CONCLUSION: Our results indicate surgery and PDT can be performed safely with very good local control. The median survival of 21.7 months, calculated from the time of surgery and PDT is encouraging. Further evaluation of this therapy is warranted.