Medical and Surgical Care of Patients With Mesothelioma and Their Relatives Carrying Germline BAP1 Mutations.

The most common malignancies that develop in carriers of BAP1 germline mutations include diffuse malignant mesothelioma, uveal and cutaneous melanoma, renal cell carcinoma, and less frequently, breast cancer, several types of skin carcinomas, and other tumor types. Mesotheliomas in these patients are significantly less aggressive, and patients require a multidisciplinary approach that involves genetic counseling, medical genetics, pathology, surgical, medical, and radiation oncology expertise. Some BAP1 carriers have asymptomatic mesothelioma that can be followed by close clinical observation without apparent adverse outcomes: they may survive many years without therapy. Others may grow aggressively but very often respond to therapy. Detecting BAP1 germline mutations has, therefore, substantial medical, social, and economic impact. Close monitoring of these patients and their relatives is expected to result in prolonged life expectancy, improved quality of life, and being cost-effective. The co-authors of this paper are those who have published the vast majority of cases of mesothelioma occurring in patients carrying inactivating germline BAP1 mutations and who have studied the families affected by the BAP1 cancer syndrome for many years. This paper reports our experience. It is intended to be a source of information for all physicians who care for patients carrying germline BAP1 mutations. We discuss the clinical presentation, diagnostic and treatment challenges, and our recommendations of how to best care for these patients and their family members, including the potential economic and psychosocial impact.

Workshop summary: Potential usefulness and feasibility of a US National Mesothelioma Registry.

The burden and prognosis of malignant mesothelioma in the United States have remained largely unchanged for decades, with approximately 3200 new cases and 2400 deaths reported annually. To address care and research gaps contributing to poor outcomes, in March of 2019 the Mesothelioma Applied Research Foundation convened a workshop on the potential usefulness and feasibility of a national mesothelioma registry. The workshop included formal presentations by subject matter experts and a moderated group discussion. Workshop participants identified top priorities for a registry to be (a) connecting patients with high-quality care and clinical trials soon after diagnosis, and (b) making useful data and biospecimens available to researchers in a timely manner. Existing databases that capture mesothelioma cases are limited by factors such as delays in reporting, deidentification, and lack of exposure information critical to understanding as yet unrecognized causes of disease. National disease registries for amyotrophic lateral sclerosis (ALS) in the United States and for mesothelioma in other countries, provide examples of how a registry could be structured to meet the needs of patients and the scientific community. Small-scale pilot initiatives should be undertaken to validate methods for rapid case identification, develop procedures to facilitate patient access to guidelines-based standard care and investigational therapies, and explore approaches to data sharing with researchers. Ultimately, federal coordination and funding will be critical to the success of a National Mesothelioma Registry in improving mesothelioma outcomes and preventing future cases of this devastating disease.

Radiologic Considerations and Standardization of Malignant Pleural Mesothelioma Imaging Within Clinical Trials: Consensus Statement from the NCI Thoracic Malignancy Steering Committee - International Association for the Study of Lung Cancer - Mesothelioma Applied Research Foundation Clinical Trials Planning Meeting.

Detailed guidelines pertaining to radiological assessment of malignant pleural mesothelioma are currently lacking due to the rarity of the disease, complex morphology, propensity to invade multiple planes simultaneously, and lack of specific recommendations within the radiology community about assessment, reporting, and follow-up. In March 2017, a multidisciplinary meeting of mesothelioma experts was co-sponsored by the National Cancer Institute Thoracic Malignancy Steering Committee, International Association for the Study of Lung Cancer, and the Mesothelioma Applied Research Foundation. One of the outcomes of this conference was the foundation of detailed, multidisciplinary consensus imaging and management guidelines. Here, we present the recommendations for radiologic assessment of malignant pleural mesothelioma in the setting of clinical trial enrollment. We discuss optimization of imaging parameters across modalities, standardized reporting, and response assessment within clinical trials.

Pathologic Considerations and Standardization in Mesothelioma Clinical Trials.

The accurate diagnosis of mesothelioma is critical for the appropriate clinical management of this cancer. Many issues complicate making the diagnosis of mesothelioma including the presence of reactive mesothelial cells in benign pleural effusions, the heterogeneity of mesothelioma histopathology, the relatively high incidence of other epithelial malignancies that metastasize to the pleura, and primary sarcomas that arise within the pleura. Given the rapidly evolving field of molecular profiling and the need for translational correlates in mesothelioma clinical trials, the National Cancer Institute (NCI)-International Association for the Study of Lung Cancer-Mesothelioma Applied Research Foundation Clinical Trials Planning Meeting was convened in March 2017 to develop a consensus on standard pathology guidelines for future NCI-sponsored clinical trials in mesothelioma. This consensus statement covers recommendations for specimen handling, pathologic classification and diagnosis, biobanking, and tissue correlative studies.

The Use of Radiation Therapy for the Treatment of Malignant Pleural Mesothelioma: Expert Opinion from the National Cancer Institute Thoracic Malignancy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation.

INTRODUCTION: Detailed guidelines regarding the use of radiation therapy for malignant pleural mesothelioma (MPM) are currently lacking because of the rarity of the disease, the wide spectrum of clinical presentations, and the paucity of high-level data on individual treatment approaches. METHODS: In March 2017, a multidisciplinary meeting of mesothelioma experts was cosponsored by the U.S. National Cancer Institute, International Association for the Study of Lung Cancer Research, and Mesothelioma Applied Research Foundation. Among the outcomes of this conference was the foundation of detailed, multidisciplinary consensus guidelines. RESULTS: Here we present consensus recommendations on the use of radiation therapy for MPM in three discrete scenarios: (1) hemithoracic radiation therapy to be used before or after extrapleural pneumonectomy; (2) hemithoracic radiation to be used as an adjuvant to lung-sparing procedures (i.e., without pneumonectomy); and (3) palliative radiation therapy for focal symptoms caused by the disease. We discuss appropriate simulation techniques, treatment volumes, dose fractionation regimens, and normal tissue constraints. We also assess the role of particle beam therapy, specifically, proton beam therapy, for MPM. CONCLUSION: The recommendations provided in this consensus statement should serve as important guidelines for developing future clinical trials of treatment approaches for MPM.

Inherited predisposition to malignant mesothelioma and overall survival following platinum chemotherapy.

Survival from malignant mesothelioma, particularly pleural mesothelioma, is very poor. For patients with breast, ovarian, or prostate cancers, overall survival is associated with increased sensitivity to platinum chemotherapy due to loss-of-function mutations in DNA repair genes. The goal of this project was to evaluate, in patients with malignant mesothelioma, the relationship between inherited loss-of-function mutations in DNA repair and other tumor suppressor genes and overall survival following platinum chemotherapy. Patients with histologically confirmed malignant mesothelioma were evaluated for inherited mutations in tumor suppressor genes. Survival was evaluated with respect to genotype and site of mesothelioma. Among 385 patients treated with platinum chemotherapy, median overall survival was significantly longer for patients with loss-of-function mutations in any of the targeted genes compared with patients with no such mutation (P = 0.0006). The effect of genotype was highly significant for patients with pleural mesothelioma (median survival 7.9 y versus 2.4 y, P = 0.0012), but not for patients with peritoneal mesothelioma (median survival 8.2 y versus 5.4 y, P = 0.47). Effect of patient genotype on overall survival, measured at 3 y, remained independently significant after adjusting for gender and age at diagnosis, two other known prognostic factors. Patients with pleural mesothelioma with inherited mutations in DNA repair and other tumor suppressor genes appear to particularly benefit from platinum chemotherapy compared with patients without inherited mutations. These patients may also benefit from other DNA repair targeted therapies such as poly-ADP ribose polymerase (PARP) inhibitors.

A Subset of Mesotheliomas With Improved Survival Occurring in Carriers of BAP1 and Other Germline Mutations.

PURPOSE: We hypothesized that four criteria could help identify malignant mesotheliomas (MMs) most likely linked to germline mutations of BAP1 or of other genes: family history of MM, BAP1-associated cancers, or multiple malignancies; or age younger than 50 years. PATIENTS AND METHODS: Over the course of 7 years, 79 patients with MM met the four criteria; 22 of the 79 (28%) reported possible asbestos exposure. They were screened for germline BAP1 mutations by Sanger sequencing and by targeted next-generation sequencing (tNGS) for germline mutations in 55 additional cancer-linked genes. Deleterious mutations detected by tNGS were validated by Sanger sequencing. RESULTS: Of the 79 patients, 43 (16 probands and 27 relatives) had deleterious germline BAP1 mutations. The median age at diagnosis was 54 years and median survival was 5 years. Among the remaining 36 patients with no BAP1 mutation, median age at diagnosis was 45 years, median survival was 9 years, and 12 had deleterious mutations of additional genes linked to cancer. When compared with patients with MMs in the SEER cohort, median age at diagnosis (72 years), median survival for all MM stages (8 months), and stage I (11 months) were significantly different from the 79 patients with MM in the current study ( P < .0001). CONCLUSION: We provide criteria that help identify a subset of patients with MM who had significantly improved survival. Most of these patients were not aware of asbestos exposure and carried either pathogenic germline mutations of BAP1 or of additional genes linked to cancer, some of which may have targeted-therapy options. These patients and their relatives are susceptible to development of additional cancers; therefore, genetic counseling and cancer screening should be considered.

Current and Future Management of Malignant Mesothelioma: A Consensus Report from the National Cancer Institute Thoracic Malignancy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation.

On March 28- 29, 2017, the National Cancer Institute (NCI) Thoracic Malignacy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation convened the NCI-International Association for the Study of Lung Cancer- Mesothelioma Applied Research Foundation Mesothelioma Clinical Trials Planning Meeting in Bethesda, Maryland. The goal of the meeting was to bring together lead academicians, clinicians, scientists, and the U.S. Food and Drug Administration to focus on the development of clinical trials for patients in whom malignant pleural mesothelioma has been diagnosed. In light of the discovery of new cancer targets affecting the clinical development of novel agents and immunotherapies in malignant mesothelioma, the objective of this meeting was to assemble a consensus on at least two or three practice-changing multimodality clinical trials to be conducted through NCI's National Clinical Trials Network.

Treatment of Malignant Pleural Mesothelioma: American Society of Clinical Oncology Clinical Practice Guideline.

Purpose To provide evidence-based recommendations to practicing physicians and others on the management of malignant pleural mesothelioma. Methods ASCO convened an Expert Panel of medical oncology, thoracic surgery, radiation oncology, pulmonary, pathology, imaging, and advocacy experts to conduct a literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 1990 through 2017. Outcomes of interest included survival, disease-free or recurrence-free survival, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. Results The literature search identified 222 relevant studies to inform the evidence base for this guideline. Recommendations Evidence-based recommendations were developed for diagnosis, staging, chemotherapy, surgical cytoreduction, radiation therapy, and multimodality therapy in patients with malignant pleural mesothelioma. Additional information is available at www.asco.org/thoracic-cancer-guidelines and www.asco.org/guidelineswiki .

Management of Malignant Peritoneal Mesothelioma Using Cytoreductive Surgery and Perioperative Chemotherapy.

Malignant peritoneal mesothelioma is a rare disease, with approximately 800 new patients per year in the United States. Its natural history is defined by progression restricted to the peritoneal space. In the past, patients with this disease had a limited lifespan of approximately 1 year. Numerous single-institution studies as well as a systematic review have reported median survival of 3 to 5 years with a combination of cytoreductive surgery and hyperthermic perioperative chemotherapy. These markedly improved survival statistics were achieved in experienced centers with 1% mortality and 20% morbidity rates. Data have shown that knowledgeable patient selection is required to prevent patients unlikely to benefit from undergoing these interventions. The conclusion is that patients with peritoneal mesothelioma can experience long-term progression-free survival or significant palliation with cytoreductive surgery plus hyperthermic perioperative chemotherapy. This management plan should be considered the standard of care for properly selected patients with malignant peritoneal mesothelioma at experienced centers around the world.

Approach to offering remote support to mesothelioma patients: the mesothelioma survivor project.

BACKGROUND: From the moment of diagnosis, malignant mesothelioma (MM) decreases health-related quality of life (QOL) in patients and their caregivers. In addition to symptoms of disease, aggressive treatments such as surgery, radiation, and chemotherapy can cause extreme side effects-chemotherapy specifically is associated with chronic fatigue, unremitting nausea, vomiting, and systemic pain. These side effects of treatments can be burdensome enough to lead to noncompliance or outright refusal of continuation of care. METHODS: The platform for the support group was remote, consisting of online and telephone domains. Participants would utilize both online and phone systems during sessions held once a week for a total of six weeks. Sessions were guided and kept closed, available only to those affected by mesothelioma. Follow-up information and session summaries were provided online after support meetings. RESULTS: Using a 0-5 Likert Scale, consistent attendees reported support groups as very helpful. Irregular attendees had mixed feelings ranging from extremely helpful to neutral. Eighty per cent of attendees participated in support groups prior to this project. CONCLUSIONS: Active participation in a guided and closed support group allowed participants to share their experiences and concerns about their diagnoses comfortably, supporting transition beyond active-treatment. Online space gave participants a place to provide more reflective responses outside the main dialogue of support sessions.

Consensus Report of the 2015 Weinman International Conference on Mesothelioma.

On November 9 and 10, 2015, the International Conference on Mesothelioma in Populations Exposed to Naturally Occurring Asbestiform Fibers was held at the University of Hawaii Cancer Center in Honolulu, Hawaii. The meeting was cosponsored by the International Association for the Study of Lung Cancer, and the agenda was designed with significant input from staff at the U.S. National Cancer Institute and National Institute of Environmental Health Sciences. A multidisciplinary group of participants presented updates reflecting a range of disciplinary perspectives, including mineralogy, geology, epidemiology, toxicology, biochemistry, molecular biology, genetics, public health, and clinical oncology. The group identified knowledge gaps that are barriers to preventing and treating malignant mesothelioma (MM) and the required next steps to address barriers. This manuscript reports the group's efforts and focus on strategies to limit risk to the population and reduce the incidence of MM. Four main topics were explored: genetic risk, environmental exposure, biomarkers, and clinical interventions. Genetics plays a critical role in MM when the disease occurs in carriers of germline BRCA1 associated protein 1 mutations. Moreover, it appears likely that, in addition to BRCA1 associated protein 1, other yet unknown genetic variants may also influence the individual risk for development of MM, especially after exposure to asbestos and related mineral fibers. MM is an almost entirely preventable malignancy as it is most often caused by exposure to commercial asbestos or mineral fibers with asbestos-like health effects, such as erionite. In the past in North America and in Europe, the most prominent source of exposure was related to occupation. Present regulations have reduced occupational exposure in these countries; however, some people continue to be exposed to previously installed asbestos in older construction and other settings. Moreover, an increasing number of people are being exposed in rural areas that contain noncommercial asbestos, erionite, and other mineral fibers in soil or rock (termed naturally occurring asbestos [NOA]) and are being developed. Public health authorities, scientists, residents, and other affected groups must work together in the areas where exposure to asbestos, including NOA, has been documented in the environment to mitigate or reduce this exposure. Although a blood biomarker validated to be effective for use in screening and identifying MM at an early stage in asbestos/NOA-exposed populations is not currently available, novel biomarkers presented at the meeting, such as high mobility group box 1 and fibulin-3, are promising. There was general agreement that current treatment for MM, which is based on surgery and standard chemotherapy, has a modest effect on the overall survival (OS), which remains dismal. Additionally, although much needed novel therapeutic approaches for MM are being developed and explored in clinical trials, there is a critical need to invest in prevention research, in which there is a great opportunity to reduce the incidence and mortality from MM.

Germline BAP1 Mutational Landscape of Asbestos-Exposed Malignant Mesothelioma Patients with Family History of Cancer.

Heritable mutations in the BAP1 tumor suppressor gene predispose individuals to mesothelioma and other cancers. However, a large-scale assessment of germline BAP1 mutation incidence and associated clinical features in mesothelioma patients with a family history of cancer has not been reported. Therefore, we examined the germline BAP1 mutation status of 150 mesothelioma patients with a family history of cancer, 50 asbestos-exposed control individuals with a family history of cancers other than mesothelioma, and 153 asbestos-exposed individuals without familial cancer. No BAP1 alterations were found in control cohorts, but were identified in nine of 150 mesothelioma cases (6%) with a family history of cancer. Alterations among these cases were characterized by both missense and frameshift mutations, and enzymatic activity of BAP1 missense mutants was decreased compared with wild-type BAP1. Furthermore, BAP1 mutation carriers developed mesothelioma at an earlier age that was more often peritoneal than pleural (five of nine) and exhibited improved long-term survival compared to mesothelioma patients without BAP1 mutations. Moreover, many tumors harboring BAP1 germline mutations were associated with BAP1 syndrome, including mesothelioma and ocular/cutaneous melanomas, as well as renal, breast, lung, gastric, and basal cell carcinomas. Collectively, these findings suggest that mesothelioma patients presenting with a family history of cancer should be considered for BAP1 genetic testing to identify those individuals who might benefit from further screening and routine monitoring for the purpose of early detection and intervention.

Combined Genetic and Genealogic Studies Uncover a Large BAP1 Cancer Syndrome Kindred Tracing Back Nine Generations to a Common Ancestor from the 1700s.

We recently discovered an inherited cancer syndrome caused by BRCA1-Associated Protein 1 (BAP1) germline mutations, with high incidence of mesothelioma, uveal melanoma and other cancers and very high penetrance by age 55. To identify families with the BAP1 cancer syndrome, we screened patients with family histories of multiple mesotheliomas and melanomas and/or multiple cancers. We identified four families that shared an identical BAP1 mutation: they lived across the US and did not appear to be related. By combining family histories, molecular genetics, and genealogical approaches, we uncovered a BAP1 cancer syndrome kindred of ~80,000 descendants with a core of 106 individuals, whose members descend from a couple born in Germany in the early 1700s who immigrated to North America. Their descendants spread throughout the country with mutation carriers affected by multiple malignancies. Our data show that, once a proband is identified, extended analyses of these kindreds, using genomic and genealogical studies to identify the most recent common ancestor, allow investigators to uncover additional branches of the family that may carry BAP1 mutations. Using this knowledge, we have identified new branches of this family carrying BAP1 mutations. We have also implemented early-detection strategies that help identify cancers at early-stage, when they can be cured (melanomas) or are more susceptible to therapy (MM and other malignancies).

Changing pattern in malignant mesothelioma survival.

UNLABELLED: Survival for mesothelioma has been shown to be poor, with marginal improvement over time. Recent advances in the understanding of pathophysiology and treatment of mesothelioma may impact therapy to improve survival that may not be evident from available clinical trials that are often small and not randomized. Therapies may affect survival differently based on mesothelioma location (pleural vs peritoneal). Data are conflicting regarding the effect of asbestos exposure on mesothelioma location. OBJECTIVES: We examined survival in a large cohort of mesothelioma subjects analyzed by tumor location and presence and mode of asbestos exposure. METHODS: Data were analyzed from cases (n = 380) diagnosed with mesothelioma from 1992 to 2012. Cases were either drawn from treatment referrals, independent medical evaluation for medical legal purposes, or volunteers who were diagnosed with mesothelioma. Subjects completed an occupational medical questionnaire, personal interview with the examining physician, and physician review of the medical record. RESULTS: This study reports better survival for mesothelioma than historical reports. Survival for peritoneal mesothelioma was longer than that for pleural mesothelioma (hazard ratio = 0.36, 95% confidence interval = 0.24-0.54, P < .001) after adjusting for gender and age at diagnosis. Non-occupational cases were more likely to be 1) diagnosed with peritoneal mesothelioma, 2) female, 3) exposed, and 4) diagnosed at a younger age and to have a 5) shorter latency compared to occupational cases (P < .001). CONCLUSION: Peritoneal mesothelioma was more likely associated with non-occupational exposure, thus emphasizing the importance of exposure history in enhancing early diagnosis and treatment impact.

Germline BAP1 mutations predispose to malignant mesothelioma.

Because only a small fraction of asbestos-exposed individuals develop malignant mesothelioma, and because mesothelioma clustering is observed in some families, we searched for genetic predisposing factors. We discovered germline mutations in the gene encoding BRCA1 associated protein-1 (BAP1) in two families with a high incidence of mesothelioma, and we observed somatic alterations affecting BAP1 in familial mesotheliomas, indicating biallelic inactivation. In addition to mesothelioma, some BAP1 mutation carriers developed uveal melanoma. We also found germline BAP1 mutations in 2 of 26 sporadic mesotheliomas; both individuals with mutant BAP1 were previously diagnosed with uveal melanoma. We also observed somatic truncating BAP1 mutations and aberrant BAP1 expression in sporadic mesotheliomas without germline mutations. These results identify a BAP1-related cancer syndrome that is characterized by mesothelioma and uveal melanoma. We hypothesize that other cancers may also be involved and that mesothelioma predominates upon asbestos exposure. These findings will help to identify individuals at high risk of mesothelioma who could be targeted for early intervention.

Phase II Study of Temozolomide and Thalidomide in Patients with Unresectable or Metastatic Leiomyosarcoma.

We assessed the efficacy of combined temozolomide and thalidomide in patients with unresectable or metastatic leiomyosarcoma in a phase II single-institution trial. Twenty-four patients were enrolled. Temozolomide (150 mg/m(2)/day for 7 days every other week) was administered with concomitant thalidomide (200 mg/day), and continued until unacceptable toxicity or disease progression. There were no complete responses and two (10%) partial responses. Five patients (24%) had stable disease for at least six months. Fourteen patients (67%) progressed after a median of two-month treatment. The median overall survival (twenty-two assessable patients) was 9.5 months [95% CI 7-28 months]. There were no treatment-related deaths or CTC grade 4 toxicities. Thirteen patients were dose-reduced or discontinued thalidomide due to toxicity. In conclusion, this combination of temozolomide and thalidomide provided disease stabilization in a subset of patients with advanced leiomyosarcoma. We hypothesize that temozolomide is the active agent in this regimen, and should be further studied.

Peritoneal mesothelioma.

OPINION STATEMENT: Malignant peritoneal mesothelioma (MPM) is an aggressive neoplasm that rapidly spreads within the confines of the abdominal cavity to involve most accessible peritoneal and omental surfaces. Current treatment options are unsatisfactory, and new approaches are needed. Recent publications have reported improved survival with an intensive loco-regional treatment strategy including cytoreductive surgery (CRS) along with hyperthermic intraperitoneal chemotherapy (HIPEC). We have noted at our institution prolonged survival in selected patients after intensive multimodality treatment. Our most recently reported trial included initial laparatomy with omentectomy, resection of peritoneal implants, and placement of bilateral peritoneal Portacath; repeated courses of intraperitoneal chemotherapy with doxorubicin, cisplatin, and interferon gamma; second-look laparotomy; and intraoperative hyperthermic perfusion with mitomycin and cisplatin, followed by whole abdominal radiation. To date there have been no universally accepted treatments for MPM. Unless referred to a specialty center, patients are routinely treated with pemetrexed and cisplatin which has been shown to increase survival in pleural mesothelioma.

Combined resection, intraperitoneal chemotherapy, and whole abdominal radiation for the treatment of malignant peritoneal mesothelioma.

OBJECTIVE: We report a single-institution Phase I or II trial of surgical debulking, intraperitoneal chemotherapy, and immunotherapy followed by whole abdominal radiotherapy in patients with malignant peritoneal mesothelioma. METHODS: Between 1997 and 2000, 27 patients with malignant peritoneal mesothelioma were enrolled: 23 with epithelial subtype and 4 with sarcomatoid or mixed subtype. The treatment regimen consisted of surgical debulking followed by 4 intraperitoneal courses of cisplatin alternating with 4 courses of doxorubicin, 4 doses of intraperitoneal gamma interferon, a second laparotomy with resection of residual disease plus intraoperative intraperitoneal mitomycin and cisplatin heated to 41 degrees C, and finally whole abdominal radiotherapy. RESULTS: The median overall survival was 70 months with a 3-year survival of 67% (95% confidence interval, 46%-81%). Fourteen patients have died of their disease with a median time to death of 17 months (range, 0.4-71 months) after consenting to treatment. Seven patients are alive without evidence of disease with a median follow-up of 90 months (range, 71-110 months), and 6 are alive with disease with a median follow-up of 86 months (range, 70-106 months). The regimen was well tolerated. There were no patients with Grade III or IV hematological toxicities, 2 patients with Grade III ototoxicity, and 3 patients with Grade III gastrointestinal toxicity. CONCLUSION: Based on the results of this study, intensive multimodality therapy appears feasible and effective in this group of patients.