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A. Rimner
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GR 02 - Difficult Mesothelioma Cases (ID 15)
- Event: WCLC 2015
- Type: Grand Rounds
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 4
- Moderators:J. de la Garza, A. Rimner, A. Tsao
- Coordinates: 9/08/2015, 14:15 - 15:45, 102+104+106
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GR02.01 - Case 1: A 70 Year Old with a Biphasic Stage I MPM (ID 1832)
14:20 - 14:40 | Author(s): H.I. Pass
- Abstract
- Presentation
Abstract:
A 70 year old retired insulator presented to the emergency room with progressive shortness of breath limiting his ability to complete his daily 5 mile runs. Physical examination reveals minimal breath sounds and dullness to percussion on the right side. The patient denies chest pain or weight loss. There is no history of cardiac disease and he is a never smoker. Family histroy reveals a brother with cured uveal melanoma. Chest radiography reveals a completely opacified right hemithorax. WBC is 7000, platelet count 245,000, and his HgB is 13.2 gms. A thoracentesis reveals 3.5 liters of serosanguinous fluid, and post thoracentesis radiograph reveals complete expansion. Fluid is sent for culture and cytology, and the patient is discharged to home with a 2 day supply analgesics. The culture report at 5 days reveals no growth and the cytology reveals atypical mesothelial hyperpplasia. Two months after his thoracentesis he returns to see his PCP with similar complaints of shortness of breath with exertion without chest pain. 1. What is the proper further management of this patient? 2. What is unusual about his family history, and what are the possible implications?
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GR02.02 - Case 2: A 65 Year Old with an Uncytoreduceable MPM (ID 1833)
14:40 - 15:00 | Author(s): P. Baas
- Abstract
- Presentation
Abstract:
Malignant Pleural Mesothelioma: A patient with unresectable disease It is generally accepted that only a minority of patient are candidates for combined modality treatment. Surgery or radiation alone is not able to achieve a complete pathological control of the tumor. Therefore most patients have to be considered for a systemic treatment. Since the nineties of last century only a slow progress has been achieved with the advent of chemotherapy. Single agents were tried but failed to achieve durable responses and did not achieve response rates over 20%. It was until the beginning of the current century that a standard therapy was defined using platin and an anti-folate. The response rate was 30-35% and the median survival increased from 9 to 13 months. Unfortunately 80% of the patients succumbed to the disease in the 2 years after chemotherapy. The new approaches that are currently available can be grossly divided into a maintenance; immunological and signal-pathway approach. For the case presented to our tumor board it is the challenge to decide which treatment is the most successful with acceptable toxicity. The choice of treatment strongly depends on the patients’ characteristics since cure is not very realistic. The standard of treatment consists of the administration of 4-6 courses of (cis)platin with pemetrexed given every 3 weeks. MPM is well known to respond slowly to chemotherapy and ongoing responses can be seen even after 6 courses of therapy. This has lead to the idea of maintenance therapy. In line with the results in NSCLC one can choose to continue with single agent pemetrexed but to date no randomized study has addressed this issue. Switch maintenance is currently under study with different drugs. The most mature phase III study is with bevacizumab (MAPS study), which showed an improvement in survival in the combination arm. This randomized study showed a very high survival in the control arm of 16 months. The addition of bevacizumab increased the OS to 18.8 months with statistical significance. The full data have not yet been presented and selection of the very best patients might account for this success. An ongoing randomized phase II study with defactinib tests the effect in a maintenance setting. The drug inhibits the Focal Adhesion Kinase pathway, rendering cells susceptible for apoptosis and it reduces the stem cells after chemotherapy. The results are expected in 2016. Since the disease recurs within 1 year, often second line therapy is offered. In table 1 a summary of different approaches is presented. Besides different chemotherapy regimens, inhibition of signal transduction pathways or immunotherapy has been tested. Until now no chemotherapeutic agent or oral TKI has been identified as promising agent. Immunotherapy however, is now one of the new and perhaps most promising developments of this decade. In this particular anti-PD-1 monoclonal antibodies and antibody drug conjugates have shown interesting results in phase I setting. There are a few issues to be resolved in the near future: How to select the best drug for each patient. How to compare study results in patients with different pathology/biological characteristics With a relatively small number of patients per year we must not embark blindly in to large phase 3 studies. We must try to personalize the treatment by increasing our TR efforts. Pre- and post-treatment biopsies can help to identify promising drugs at an early stage. Pre-treatment cell cultures can help to improve the selection of patients who might be good responders to certain chemical compounds. And finally we must improve our collaboration between centers to offer optimal service to our patients. Table 1
cis: cisplatin; pem: pemetrexed; vin: vinorelbine; bev: bevacizumab; a-CTL4: anti cytotoxic lymphocyte 4; a-PD1: anti-programmed death; LoE: level of evidence; PFS: progression free survival Selected references 1.Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. J Clin Oncol 2003;21:2636–44 2, Jassem J, Ramlau R, Santoro A, et al. J Clin Oncol 2008;26:1698-1704 3. Zalcman et al. pASCO 2015 4. Hassan R, Miller AC, Sharon E et al. Sci Transl Medicine. 2013;5(208):208ra147. 5. Alley E et al. pAACR 2015Agent group line Recommended Agents LoE Remark Chemotherapy 1 cis/pem I Standard since 2003 (1) 2 pem; vin II pem showed improved PFS (2) Maintenance 1 bev I Reported at ASCO 2015 (3) TKI 2 none - Many tested; no conclusive results Immunotherapy 2 Immunotoxins III Phase I study of pseudomonas toxin (4) a-CTL4; a-PD1 III Trametinib now tested in maintenance setting in phase III; pembrolizumab showed promising results in phase I (5)
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GR02.03 - Case 3: A 65 Year Old with a Clinical Stage II MPM and Chest Pain (ID 1834)
15:00 - 15:20 | Author(s): J. Friedberg
- Abstract
- Presentation
Abstract not provided
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GR02.04 - Addressing the Needs of the Mesothelioma Patient Who Has Exhausted Treatment Options: Palliation and Support for Family and Patient (ID 1835)
15:20 - 15:45 | Author(s): H. Clayson, L. Darlison, M. Hesdorffer
- Abstract
Abstract:
The care of people with end-stage mesothelioma is complex due to the interplay of severe physical symptoms, intense psychological distress, and social factors related to mesothelioma being a fatal occupational disease. In comparison with people suffering from lung cancer, patients with mesothelioma experience more pain and greater negative impact on role and functioning and insomnia (1). Patients and family members should expect effective management of symptoms, support during the continuum of the illness and a rapid response to crisis. The high symptom burden experienced by patients with mesothelioma in the last year of life is shown in the table below (2):
Patients with incurable disease deserve and need to receive clear information and to share in the decision-making about each stage of their cancer journey. Once oncological treatments are exhausted, healthcare professionals hold the responsibility for helping patients and their families shift their expectation from “cure” to palliation of symptoms. A care plan for a good death needs to be sensitively eased into the clinical discussions, taking into account each individual patient’s preferences (3). In rare diseases such as mesothelioma a feeling of isolation tends to overwhelm the patient and their family. Unlike most cancers mesothelioma has an explained occupational and/or environmental cause. In many cases understanding that the fatal illness was caused by asbestos exposure due to neglect of health and safety precautions at work can lead to blame, anger, depression and inability to cope. The complicated processes concerning claims for welfare benefits and civil compensation litigation often exacerbate this psychological distress. Meeting the care needs of patients and their families in this situation requires a compassionate and specialised multi-disciplinary approach. Expert timely supportive and palliative care can address the burdens associated with advanced disease and guide the patient and family in accepting and planning for a good death. Transition to focus care on the family during the grief process completes the cycle in the care of the mesothelioma patient and family. Panel discussion will include the following areas: · Advanced education and the expanded role of a nursing team solely focused on mesothelioma (4). · The roles and availability of on-line, in person and telephone support groups · The need for early referral into palliative, supportive and hospice care References 1. Nowak AK, Stockler MR, Byrne MJ (2004) Assessing quality of life during chemotherapy for pleural mesothelioma: feasibility, validity, and results of using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire and Lung Cancer Module. J Clin Oncol. Aug 1;22 (15):3172-80. 2. Clayson H (2007) Thesis: The Experience of Mesothelioma in Northern England. University of Sheffield. Available online at etheses.whiterose.ac.uk/1775/ 3. Pass HI, Hesdorfer M, Lake SE, Lake SA. (2012) 100 Questions and Answers about Mesothelioma. Third Edition 4. Moore S, Darlison L (2011) Improving the nursing care of patients with mesothelioma. Nurs Stand May 25-31;25(38):35-8Pleural mesothelioma: Symptoms in the last year of life Breathlessness 96% Social 16% Pain 91% Nausea 14% Cough 41% Fatigue 13% Weight loss 41% Dysphagia 11% Anxiety 31% Psychiatric 10% Anorexia (loss of appetite) 25% Constipation 8% Depression 19% Ascites 8% Sweating 18% Vomiting 5% Emotional disturbance 16% Painful metastasis 5%
Author of
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MINI 38 - Biology and Prognosis (ID 167)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:R. Tsuchiya, M. Wynes
- Coordinates: 9/09/2015, 18:30 - 20:00, 702+704+706
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MINI38.02 - BAP1 Inactivation in Mesothelioma Is Highly Prevalent (ID 657)
18:35 - 18:40 | Author(s): A. Rimner
- Abstract
- Presentation
Background:
Efforts to elucidate tumorigenic mutations in mesothelioma are essential to advance therapy. Prior efforts to characterize the molecular heterogeneity of this disease have been limited by sample condition and testing platforms. Herein, we describe efforts to prospectively test patients using next-generation sequencing with matched patient germline controls.
Methods:
Sequential mesothelioma patients were approached for consent to our IRB protocol NCT01775072 to perform MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets), a comprehensive molecular profiling platform based on solution-phase exon capture and next generation sequencing to detect somatic genetic alterations in FFPE tumor specimens. MSK-IMPACT involves hybridization capture and deep sequencing of all protein-coding exons of 341 key cancer-associated genes, including all genes that are druggable by approved therapies or are targets of experimental therapies being investigated in clinical trials at MSKCC.
Results:
51 patients with mesothelioma underwent MSK-IMPACT testing (see Table 1). 12 samples had low tumor content. Among 39 samples with reliable results, BAP1 was the most common alteration (46%). Another 3 samples had changes also thought to inactivate BAP1 (2 samples had gene copy number changes just below the cutoff for whole gene deletions and 1 had an inversion of LIMD-BAP1 thought to inactivate BAP1), making the incidence of BAP1 alterations possibly as high as 56%. In 4 samples with sufficient tumor content, no alterations were identified. Table 1N=39 (%) Gender M/F 26/13 (67/33) Primary site of disease * Pleural * Peritoneal * Testicular 32 (82) 6 (15) 1 (3) # identified alteration, average 3 Alterations present in >6% * BAP1 * NF2 * CDKN2Ap16INK4A * SETD2 * CDKN2Ap14ARF * LATS1 * CREBBP * WT1 * CDKN2B * PI3KCA * PBRM1 * TP53 18 (46) 8 (21) 5 (13) 5 (13) 4 (10) 4 (10) 4 (10) 4 (10) 3 (8) 3 (8) 3 (8) 3 (8)
Conclusion:
Using MSK-IMPACT, BAP1 inactivation is the most common alteration. Other aberrations previously reported at high frequency were identified but albeit at lower frequencies (NF2 and p16, previously reported as 40% and 75% respectively). For multiple samples with deep coverage, no alterations were identified. The high incidence of BAP1 mutations in this systematic testing makes this pathway ideal for developing and testing targeted therapies.
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ORAL 26 - Clinical Trials 2 (ID 127)
- Event: WCLC 2015
- Type: Oral Session
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:A. Scherpereel, C. Thomas
- Coordinates: 9/08/2015, 10:45 - 12:15, 702+704+706
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ORAL26.08 - Discussant for ORAL26.05, ORAL26.06, ORAL26.07 (ID 3363)
12:01 - 12:11 | Author(s): A. Rimner
- Abstract
- Presentation
Abstract not provided
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P1.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 212)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.03-004 - Occult Primary Non-Small Cell Lung Cancer with Mediastinal Lymph Node Involvement (ID 1573)
09:30 - 09:30 | Author(s): A. Rimner
- Abstract
Background:
Non-small cell lung cancer (NSCLC) involving mediastinal lymph nodes without an identifiable primary tumor is a rare presentation. While definitive surgery or radiotherapy with or without concurrent chemotherapy is typically recommended, little is known about the treatment outcomes. As such, we reviewed our institutional experience to determine if subsequent development of lung tumors is common and whether prognosis is comparable to stage III NSCLC in general.
Methods:
This study was an IRB-approved retrospective review of an institutional NSCLC database. Twenty-six patients with biopsy-proven NSCLC involving mediastinal lymph nodes with no identifiable lung primary lesion and no evidence of distant metastases treated with curative intent between 1995-2013 were identified. PET-CT staging was performed in 25 of 26 patients. All followup was calculated from date of diagnosis.
Results:
The median followup was 44 months. The median age at diagnosis was 60 years (range 51-81) among the 18 males (69%) and 8 females (31%). N2 and N3 disease were each present in 13 (50%) patients, respectively. Histologies included adenocarcinoma in 12 (46%), squamous cell carcinoma in 10 (38%), NSCLC not otherwise specified in 3 (12%), and large cell lung carcinoma in 1 (4%). Eleven patients underwent EGFR mutation analysis, with no sensitizing mutations identified. All patients had a smoking history (median 35 pack-years). Four (15%) patients underwent complete surgical resection, of whom 3 underwent induction chemotherapy and 1 was treated with surgery alone. One of the four patients underwent post-operative radiation therapy to 54 Gy. Twenty-two (85%) patients were treated with definitive radiation therapy including sequential chemotherapy and radiation in 8 (mean RT dose = 70 Gy), concurrent chemoradiation in 10 (mean RT dose = 60 Gy), neoadjuvant chemotherapy followed by concurrent chemoradiation in 3 (mean RT dose = 66 Gy), and radiation alone in 1 (treated to 60 Gy). The median overall survival was 78.1 months with actuarial 2- and 5-year survival rates of 78% and 67%, respectively. Five patients developed intrathoracic failure at a median of 19.8 months. One patient had an isolated lung failure at 13.6 years, but this likely represents a secondary primary and not tumor recurrence. Two patients had isolated mediastinal lymph node failures at 18.1 and 19.8 months and 2 patients initially had a mediastinal lymph node recurrence at 0.2 and 3.4 years, but subsequently failed in the lung at 8.5 and 3.6 years respectively. The actuarial 2- and 5-year intrathoracic control rates were 85.7% and 78.6%. Nine patients developed metastatic disease at a median of 16.5 months. The 2- and 5-year actuarial freedom from distant metastases was 70.9% and 59.1%. Among patients receiving definitive radiation, there was no difference between those receiving concurrent chemotherapy and those who did not.
Conclusion:
To our knowledge, this is the largest reported series of occult primary NSCLC involving mediastinal nodes. Definitive local therapy, including radiotherapy and surgery, was associated with very favorable locoregional control and survival, particularly compared with expected outcomes for stage III NSCLC.
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P1.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 224)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.08-022 - Intraoperative Brachytherapy for Thoracic Malignancies Resected with Close or Positive Margins (ID 2795)
09:30 - 09:30 | Author(s): A. Rimner
- Abstract
Background:
Local recurrence is a significant problem after surgical resection of thoracic tumors, particularly when close or positive margins are anticipated. As intraoperative radiotherapy (IORT) can deliver radiation directly to the threatened margin, we used this technique in an attempt to reduce local recurrence, particularly for patients who had already received external beam radiation. We updated our experience with thoracic IORT to assess disease control and toxicity outcomes.
Methods:
We performed a retrospective review of patients undergoing permanent I-125 mesh placement or temporary Ir-192 afterloading therapy during surgical resection of primary or metastatic thoracic tumors between 2001 and 2013. In general, for I-125 brachytherapy, iodine seeds were sutured into a mesh at 1cm intervals to form a planar implant delivering 85-250Gy to the MPD, which was then sutured onto the at-risk site. For Ir-192 brachytherapy, a HAM applicator was apposed to the at-risk site, then connected to the afterloader to deliver 7.5-16Gy to a depth of 0.5cm from the applicator surface. Kaplan-Meier method was used to estimate local control and overall survival, and logrank test was used to assess the impact of various clinical or treatment factors on local control.
Results:
Fifty-nine procedures (41 permanent, 18 temporary) were performed on fifty-eight patients (median 56 years old, range 19-77). Most common tumor histologies were NSCLC (n=23), sarcoma (n=18), thymic carcinoma (n=10), and mesothelioma (n=3). Treated sites were chest wall/paraspinal (n=31), lung (n=16), and mediastinum (n=12). Thirty-four procedures were performed on patients who had previously received external beam RT (EBRT) to the area (median 53.1 Gy). Final margins were microscopically negative in 25 cases (42.4%) and positive or not assessed in the remainder. The median size of the treated area was 27cm[2] (range: 4-152cm[2]). Median followup was 28.5 months. Actuarial local control at 1 and 2 years was 68.1% and 63.4% respectively. Median survival was 46.2 months. Overall survival at 1 and 2 years was 80.2% and 70.4% respectively. No perioperative deaths occurred. There was no significant difference in local control according to margin status, brachytherapy technique, use of adjuvant EBRT, or metastatic vs. primary tumor. Two patients (3.4%) experienced grade 3+ toxicities possibly related to IORT: one patient who also received preoperative EBRT developed pneumonitis; a second patient with prior EBRT for lymphoma died from complications of SVC syndrome likely induced by radiation fibrosis. An additional 8 patients had grade 3+ postsurgical complications (such as empyema, chylothorax, and pulmonary emboli) unlikely related to IORT. Four patients had grade 2 nerve injury also unlikely related to IORT.
Conclusion:
Intraoperative brachytherapy is associated with good local control after resection of thoracic tumors felt to be at very high risk for recurrence due to close or positive margins. There is a very low incidence of severe toxicity attributable to brachytherapy. Intraoperative brachytherapy should be considered in situations where the oncologic completeness of thoracic tumor resection is in doubt.
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P2.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 213)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.03-032 - Prognostic Impact of EGFR and KRAS Mutations in Patients with Lung Adenocarcinoma Treated with Definitive Radiation Therapy (ID 2422)
09:30 - 09:30 | Author(s): A. Rimner
- Abstract
Background:
An association of EGFR and KRAS mutations with radiation sensitivity has been postulated in preclinical studies. Recent clinical studies reported longer local control and survival in patients (pts) harboring EGFR mutations treated with definitive radiotherapy (RT). Here, we sought to evaluate the prognostic impact of EGFR and KRAS mutations in 223 adenocarcinoma pts treated with definitive RT at our institution.
Methods:
Between 2004 and 2013, 466 inoperable pts with non-squamous lung cancer were treated with definitive RT ± chemotherapy. Mutational testing was performed in 223 pts. 44% were male, 56% female. 65% were former, 13% never, and 22% current smokers. Clinical stage was II in 5%, IIIA in 37% and IIIB in 58%. Median size of tumor was 3.8 cm (range 0.5-12.2 cm). 60% received concurrent, 31% sequential chemo-RT and 9% RT alone. The median RT dose was 63Gy (range 50-80Gy). OS was estimated by the Kaplan-Meier method. Cumulative incidence functions were used to estimate local failure (LF) and distal failure (DF), using death without failure as a competing risk. Association of factors with OS was analyzed by Cox regression and association with LF and DF by competing risk regression.
Results:
EGFR status was wild-type in 205 pts (92%) and mutated in 18 (8%). The most common EGFR mutations were exon 19 deletion (8 pts), followed by exon 21 L858R (7 pts), and exon 20 insertion (3 pts). KRAS status was wild- type in 142 pts (64%), mutated in 63 (28%), and not performed in 18 (8%). The most common mutations were G12C (13%), followed by G12V (5%) and G12A and G12D (3% each). With a median follow-up among survivors of 32.7 months (range 0.6-114), the median OS was 38 months for pts with EGFR mutation versus 26 months for pts without (p=0.96); 21 months for patients with KRAS mutation versus 31 months for pts without (p=0.24). 2-year LF was 37% and 46% for pts with and without EGFR mutation, and 48% and 46% for pts with and without KRAS mutation, respectively. 2-year DF was 80% and 64% for pts with and without EGFR mutation, and 62% and 64% for pts with and without KRAS mutation, respectively. On univariate analysis, factors significantly associated with improved OS included KPS ≥ 80 (p=0.01), increasing RT dose (p=0.04) and use of concurrent chemotherapy compared to RT alone (p=0.001). Factors associated with higher risk of LF included stage IIIB (p=0.04) and sequential rather than concurrent chemotherapy (p=0.05). Factors associated with a higher risk of DM included stage IIIB (p=0.03) and lower RT dose (p=0.003). Association of EGFR and KRAS mutations did not reach statistical significance on univariate analysis, thus we did not further investigate their effects by multivariable analysis.
Conclusion:
Despite analyzing the largest patient population to date, we did not identify a significant prognostic impact by EGFR or KRAS mutational status. The lack of an observed association could be related to the low rate of EGFR mutations identified. RT dose and use of concurrent chemotherapy were significantly associated with overall survival.
