bims-mesote Biomed News
on Mesothelioma
Issue of 2021–10–31
fourteen papers selected by
Laura Mannarino, Humanitas Research
  1. Carbon Dioxide Blower Facilitates Visceral Pleurectomy in Malignant Pleural Mesothelioma.
  2. Prediction modeling using routine clinical parameters to stratify survival in malignant pleural mesothelioma patients complicated with malignant pleural effusion.
  3. A New Pretreatment Mesothelioma Risk Score: Integrating Clinical and Molecular Factors for Predicting Outcomes in Malignant Pleural Mesothelioma.
  4. Treatment patterns and outcomes in older patients with advanced malignant pleural mesothelioma: Analyses of Surveillance, Epidemiology, and End Results-Medicare data.
  5. JME-001 phase II trial of first-line combination chemotherapy with cisplatin, pemetrexed, and nivolumab for unresectable malignant pleural mesothelioma.
  6. Multivariate Model for Predicting Overall Survival in Malignant Pleural Mesothelioma After Adjuvant Radiotherapy.
  7. A Phase III Randomized Trial of Pleurectomy/Decortication Plus Chemotherapy With or Without Adjuvant Hemithoracic Intensity-Modulated Pleural Radiation Therapy (IMPRINT) for Malignant Pleural Mesothelioma (MPM) (NRG LU-006).
  8. Impact of Tumor Treating Fields (TTFields) on DNA Damage Repair in Mesothelioma.
  9. Conspicuity of malignant pleural mesothelioma in contrast enhanced MDCT - arterial phase or late phase?
  10. [Recommendations for the management of malignant pleural mesothelioma].
  11. Segmentation of the Upper Torso for Lung Cancer TTFields Treatment Planning.
  12. Creating Computational Models for Planning TTFields Treatment for Tumors in the Infratentorial Brain.
  13. Treating Spinal-Cord Tumors with TTFields - A Simulation Study.
  14. Activated Phosphoinositide 3-Kinase/AKT/mTOR Signaling Confers Resistance to Tumor Treating Fields (TTFields).
  1. Ann Thorac Surg. 2021 Oct 26. pii: S0003-4975(21)01762-8. [Epub ahead of print]
    Carbon Dioxide Blower Facilitates Visceral Pleurectomy in Malignant Pleural Mesothelioma.
    Jie Dai, Ming Liu, Xiaogang Liu, Jiaqi Li, Kaiqi Jin, Linsong Chen, Minwei Bao, Gening Jiang.
      Pleurectomy/decortication serves as a major component of therapy for malignant pleural mesothelioma (MPM), but the procedure is time consuming. We tentatively applied carbon dioxide (CO2) blower into pleurectomy/decortication for a patient with local relapse of MPM. The blower can help increase the potential subpleural place thanks to the positive pressure by CO2, while the mist of saline could clean the potential bleeding to increase visibility. Thereby, the procedure was greatly facilitated in a more precise manner, with blood loss of 100ml and acceptable postoperative air leak and thorax drainage. Therefore, CO2 blower may be considered in pleurectomy/decortication for MPM.
    Keywords:  Carbon dioxide blower; Malignant pleural mesothelioma; Pleurectomy
    DOI:  https://doi.org/10.1016/j.athoracsur.2021.09.046
  2. Thorac Cancer. 2021 Oct 26.
    Prediction modeling using routine clinical parameters to stratify survival in malignant pleural mesothelioma patients complicated with malignant pleural effusion.
    Shu Zhang, Yuan Zhang, Wei Feng, Zhongyue Shi, Huanzhong Shi, Yuhui Zhang.
       BACKGROUND: Malignant pleural effusion (MPE) is common in malignant pleural mesothelioma (MPM). The survival of patients with MPM and MPE is heterogeneous. The LENT and BRIMS scores using routine clinical parameters were developed to predict the survival of patients with unselected MPE and MPM, respectively. This study aimed to stratify the survival of selected MPM patients with MPE.
    METHODS: Data were collected from subjects diagnosed with MPM and MPE. The LENT and BRIMS scores were applied using a combination of clinical variables to stratify subjects and compare survival characteristics.
    RESULTS: In total, 101 patients with MPM complicated by MPE were included in the study. The median follow-up time was 71 months (interquartile range: 24-121 months). Overall median survival was 24 (interquartile range: 12-52 months). Based on the LENT score, the low-, moderate-, and high-risk groups accounted for 65.3% (66 cases), 34.7% (35 cases), and 0%, respectively. The cumulative survival rates of the two groups were statistically significant (p = 0.031). The area under the curve (AUC) of the LENT score was 0.662. Based on the BRIMS score, the first, second, third, and fourth risk groups accounted for 1.0% (1 case), 42.9% (35 cases), 28.7% (29 cases), and 19.4% (36 cases), respectively. Survival was significantly higher in patients in the risk groups 1 and 2 than in patients in the risk groups 3 and 4 (p  = 0.037). The AUC of the BRIMS score was 0.605.
    CONCLUSIONS: Using routinely available clinical variables, both LENT and BRIMS scores could stratify selected MPM and MPE patients into risk groups with statistically different survival.
    Keywords:  BRIMS score; LENT score; malignant pleural effusion; malignant pleural mesothelioma; prognosis
    DOI:  https://doi.org/10.1111/1759-7714.14202
  3. J Thorac Oncol. 2021 Nov;pii: S1556-0864(21)02323-6. [Epub ahead of print]16(11): 1782-1784
    A New Pretreatment Mesothelioma Risk Score: Integrating Clinical and Molecular Factors for Predicting Outcomes in Malignant Pleural Mesothelioma.
    Rafael López-Castro, Gonzalo Recondo, Teresa Gorría, Laura Mezquita.
      
    DOI:  https://doi.org/10.1016/j.jtho.2021.07.010
  4. Cancer Rep (Hoboken). 2021 Oct 26. e1568
    Treatment patterns and outcomes in older patients with advanced malignant pleural mesothelioma: Analyses of Surveillance, Epidemiology, and End Results-Medicare data.
    Mark D Danese, Melinda Daumont, Esmond Nwokeji, Michelle Gleeson, John R Penrod, Deborah Lubeck.
       BACKGROUND: Malignant mesothelioma is a rare neoplasm associated with asbestos exposure. Characterizing treatment patterns and outcomes of older patients with advanced malignant pleural mesothelioma (MPM) is important to understand the unmet needs of this population.
    AIM: To evaluate the demographic and clinical characteristics, treatment patterns, and outcomes among older patients diagnosed with advanced MPM in the United States between 2007 and 2013.
    METHODS: This was a retrospective cohort study using Surveillance, Epidemiology, and End Results (SEER) data linked with Medicare claims. We included patients who were age 66 or older at the time of their primary MPM diagnosis between 2007 and 2013 and followed them through 2014. Treated patients who received first-line chemotherapy with pemetrexed and platinum within 90 days of diagnosis, second-line, or third-line therapy were identified for evaluation of outcomes.
    RESULTS: There were 666 older patients with advanced MPM, of whom 82% were male, 87% White, 78% stage IV, and 70% had no mobility limitation indicators at diagnosis. There were 262 patients who received first-line chemotherapy for advanced MPM, most of whom (80%; n = 209) received pemetrexed-platinum. Of these 209 patients, 41% (n = 86) initiated second-line therapy, and 26% (n = 22) initiated third-line therapy. Median overall survival for the cohort of 209 patients was 7.2 months. Patients with epithelioid histology had better median overall survival (12.2 months) compared with other histologies (4.4-5.6 months). Within 90 days of diagnosis of advanced MPM, 78% of patients were hospitalized, 52% visited an emergency department, and 21% had hospice care. The 2-year cost of care was over $100 000 for all patients with advanced MPM treated with first-line pemetrexed-platinum.
    CONCLUSIONS: Although first-line systemic anticancer treatment was generally consistent with guidelines (e.g., pemetrexed-platinum), poor patient outcomes highlight the need for effective treatment options for older patients with advanced MPM.
    Keywords:  Epidemiology; Surveillance; and End Results; costs; mesothelioma; overall survival; treatment
    DOI:  https://doi.org/10.1002/cnr2.1568
  5. J Immunother Cancer. 2021 Oct;pii: e003288. [Epub ahead of print]9(10):
    JME-001 phase II trial of first-line combination chemotherapy with cisplatin, pemetrexed, and nivolumab for unresectable malignant pleural mesothelioma.
    Yosuke Miyamoto, Toshiyuki Kozuki, Keisuke Aoe, Sae Wada, Daijiro Harada, Michihiro Yoshida, Jun Sakurai, Katsuyuki Hotta, Nobukazu Fujimoto.
       BACKGROUND: JME-001 is a phase II trial assessing the efficacy and safety of cisplatin, pemetrexed, and nivolumab as first-line therapy in malignant pleural mesothelioma (MPM).
    PATIENTS AND METHODS: Patients with untreated, unresectable MPM with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 were included. The primary endpoint is the centrally reviewed objective response rate. The secondary endpoints include (1) response rate assessed by investigators, (2) disease control rate, (3) overall survival, (4) progression-free survival, (5) duration of response, and (6) time to response. Safety and adverse events will also be evaluated. Cisplatin (75 mg/m2), pemetrexed (500 mg/m2), and nivolumab (360 mg/body) were administered intravenously every 3 weeks with a total of 4-6 cycles. If patients did not progress during the combination phase, maintenance therapy with nivolumab was administered until disease progression or unacceptable toxicity. Tissue samples were required and collected for programmed death ligand 1 analysis.
    RESULTS: Eighteen patients (mean age 69.2 years, 15 men) were enrolled between January 2018 and May 2019. The ECOG PS was 0 in 3 patients and 1 in 15 patients. Fourteen (77.8%; 95% CI 52.4% to 93.6%) patients had an objective response. The disease control rate was 94.4% (95% CI 72.7% to 99.9%). Fourteen (77.8%) patients had partial response (PR), three had stable disease, and one was not evaluable. Tumor shrinkage was observed in 10/14 (71.4%) patients with epithelioid, and 2/2 (100%) patients with sarcomatoid or biphasic histological subtype had PR. Ten (55.6%) patients experienced grade 3 or worse adverse events, including disorder of metabolism or nutrition (33.3%), loss of appetite (27.8%), anemia (16.7%), and hyponatremia (11.1%). No treatment-related deaths occurred.
    CONCLUSIONS: The safety and efficacy of this study strongly support a definitive trial of this combination.Trial registration numberUMIN000030892.
    Keywords:  clinical trials; phase II as topic
    DOI:  https://doi.org/10.1136/jitc-2021-003288
  6. Int J Radiat Oncol Biol Phys. 2021 Nov 01. pii: S0360-3016(21)01435-8. [Epub ahead of print]111(3S): e131-e132
    Multivariate Model for Predicting Overall Survival in Malignant Pleural Mesothelioma After Adjuvant Radiotherapy.
    V R Li, Z Wang, V Y Yu, R V Dams, R Philipson, P Lee, A U Kishan, A Lee, X Qi.
       PURPOSE/OBJECTIVE(S): Malignant pleural mesothelioma (MPM) is a rare but aggressive cancer arising from the cells of the thoracic pleura. Its anatomic complexity, large surface area, and unique location pose challenges for target coverage while sparing adjacent organs at risk (OARs) during treatment planning for adjuvant radiotherapy after pleurectomy and decortication. We aimed to investigate the associations between patient/target characteristics and achievable dosimetric plan quality with overall survival.
    MATERIALS/METHODS: Sixty patients with MPM patients who were treated on a tomotherapy unit between 2013-2018 at a single institution were included. All patients received helical IMRT with 45 Gy/25 fractions. Dosimetric quantities for the lungs, heart, and liver were systematically examined for 37 right-sided (RSM) and 23 left-sided mesothelioma (LSM) patients. Patient characteristics and/or planning dosimetric metrics were input into machine learning algorithms, e.g., LASSO regression, support vector machine (SVM), and multiple layer perceptron (MLP), in order to construct predictive models for overall survival. The performance of predictive models was evaluated with area under the curve (AUC) using 3-fold cross validation. Normal tissue complication probabilities (NTCP) for selected OARs were estimated using the Lyman-Kutcher-Burman model based on individual dose volume histograms.
    RESULTS: The achieved dosimetric endpoints were significantly different (P < 0.05) between LSM vs. RSM patients, respectively: ipsilateral lung V20Gy of 91.2 ± 6.7 vs. 85.3 ± 6.5%, ipsilateral mean lung doses of 39.1 ± 3.8 vs. 36.9 ± 2.5 Gy, heart mean doses of 25.2 ± 3.6 vs. 18.8 ± 3.7 Gy, and liver mean doses of 10.6 ± 2.7 vs. 23.4 ± 4.2 Gy. There was no significant difference in total lung - planning target volume (PTV) mean dose, 13.4 ± 2.0 vs. 14.4 ± 1.5 Gy, nor expected lung pneumonitis for the LSM vs. RSM. No differences were observed between PTV coverage of 94.2 ± 1.2 vs. 93.4 ± 2.4%, and average survival intervals were 16.8 ± 14.4 months and 18.0 ± 18.0 months after RT between LSM vs. RSM. The MLP model achieved AUCs of 0.65, 0.67 and 0.71 using patient characteristics, dosimetric features, and combined features. The identified predictors most associated with overall survival were age, PTV volume, ipsilateral lung volume/V20Gy, and ipsilateral lung - PTV V20Gy CONCLUSION: We demonstrated correlations between patient specific characteristics and achieved planning dosimetric parameters for left- and right-sided MPM treatment planning endpoints. Combining patient characteristics and dosimetric endpoints, the multivariate predictive model achieved decent performance in predicting overall survival. The predictive model may guide treatment planning to achieve optimal planning dosimetry, and to improve clinical outcome via personalized treatment for MPM.
    DOI:  https://doi.org/10.1016/j.ijrobp.2021.07.565
  7. Int J Radiat Oncol Biol Phys. 2021 Nov 01. pii: S0360-3016(21)02168-4. [Epub ahead of print]111(3S): e463-e464
    A Phase III Randomized Trial of Pleurectomy/Decortication Plus Chemotherapy With or Without Adjuvant Hemithoracic Intensity-Modulated Pleural Radiation Therapy (IMPRINT) for Malignant Pleural Mesothelioma (MPM) (NRG LU-006).
    A Rimner, C Hu, V W Rusch, R R Gill, C B Simone Ii, M Zauderer, E D Yorke, Z Li, T D Peikert, R Voong, M Tsao, J D Bradley.
       PURPOSE/OBJECTIVE(S): Pleurectomy/Decortication (P/D) has become a common lung-sparing surgical approach for MPM. Chemotherapy may be delivered in the neoadjuvant or adjuvant setting. Adjuvant hemithoracic IMPRINT was developed at Memorial Sloan Kettering Cancer Center and found safe in a multi-institutional phase II study, with promising survival outcomes. CTEP approved a phase III randomized cooperative group trial (NRG LU-006) to evaluate the efficacy of this lung-sparing trimodality treatment approach for resectable MPM.
    MATERIALS/METHODS: Patients with newly diagnosed MPM amenable to P/D are enrolled and undergo upfront P/D followed by adjuvant platinum/pemetrexed chemotherapy (preferred approach) or neoadjuvant chemotherapy followed by P/D. Patients are stratified by epithelioid vs. biphasic histologic subtype, achievement of a macroscopic complete resection (R0/1 vs. R2), and center patient volume (≤10 vs. > 10 P/Ds per year). Within 8 weeks after completion of the second modality, patients are randomized 1:1 to undergo hemithoracic IMPRINT vs. no further therapy. All IMPRINT contours and treatment plans are centrally reviewed. A contouring atlas and treatment planning constraints for target structures and organs at risk, including acceptable and unacceptable variations and deviations, were developed. Photon and proton therapy are permitted. The primary endpoint of the study is overall survival. Secondary endpoints include local failure-free, distant-metastases free and progression-free survival, treatment-related toxicities (CTCAE v5.0) and change in quality-of-life (EORTC QLQ-C30 mean score changes at 9 months post randomization). Exploratory objectives include correlation of clinical/radiographic staging with pathologic stage, immunologic and pathologic biomarkers as predictors of response, the rate of R0/R1 vs. R2 resections, and EORTC QLQ-C30 and LC13 symptom scores changes over time. This study was activated on January 29, 2020. As of 02/2021,16 sites are approved and 46 sites are pending approval to open the study. Treatment planning guidelines and helpful hints for photon and proton therapy will be presented. Two patients have been accrued, and the target accrual is 150 patients.
    RESULTS: TBD CONCLUSION: NRG LU-006 is now open to accrual. This is the first NRG Oncology randomized phase III trial on malignant pleural mesothelioma and evaluates the use of IMPRINT following lung-sparing P/D and chemotherapy. Treatment planning aspects and current status will be presented.
    DOI:  https://doi.org/10.1016/j.ijrobp.2021.07.1298
  8. Int J Radiat Oncol Biol Phys. 2021 Nov 01. pii: S0360-3016(21)02167-2. [Epub ahead of print]111(3S): e463
    Impact of Tumor Treating Fields (TTFields) on DNA Damage Repair in Mesothelioma.
    H Mumblat, A Martinez-Conde, O Braten, M Munster, E Dor-On, R S Schneiderman, Y Porat, T Voloshin, S Davidi, R Blatt, A Shteingauz, C Tempel Brami, E Zeevi, C Lajterer, Y Shmueli, S Danilov, A Haber, M Giladi, U Weinberg, Y Palti.
       PURPOSE/OBJECTIVE(S): Tumor Treating Fields (TTFields) are low intensity (1-3 V/cm), intermediate frequency (100-500 kHz), alternating electric fields delivered to solid tumors noninvasively and locoregionally. TTFields have demonstrated a promising median overall survival in patients with malignant pleural mesothelioma (MPM), an aggressive thoracic cancer with poor prognosis, without increases in systemic toxicity (STELLAR clinical trial). Consequently, TTFields therapy combined with pemetrexed and a platinum-based chemotherapy agent are approved as first line treatment for unresectable MPM in the US and Europe. While efficacy of TTFields for MPM treatment is well-established, the underlying mechanism of action needs further elucidation. This study investigated the TTFields effect on DNA damage and repair in MPM and tested the combination of TTFields with DNA damaging agents such as cisplatin and pemetrexed, in vitro and in vivo.
    MATERIALS/METHODS: TTFields frequencies ranging from 100-400 kHz were applied to human MPM cell lines (NCI-H2052 and MSTO-211H) to identify the most effective frequency. To detect DNA double strand breaks (DSB), the effect of optimal TTFields frequency on the formation of ɣH2AX foci was examined by fluorescent microscopy. Levels of DNA damage repair related proteins were evaluated via immunoblotting of cell lysates. The combined cytotoxic effect of TTFields with cisplatin or pemetrexed was tested in vitro. Efficacy of TTFields concomitant with both cisplatin and pemetrexed was examined in C57BL/6 mice inoculated subcutaneously with RN-5 cells by measuring tumor volume and DNA damage within the tumor.
    RESULTS: The optimal TTFields frequency was identified as 150 kHz in both MPM cell lines, displaying significant cytotoxicity and formation of DNA DSB. These effects were accompanied by increased expression of p21 and p27, proteins involved in DNA damage-induced cell cycle arrest, and reduced expression of proteins from the Fanconi Anemia (FA) DNA repair pathway - FANCA, FANCD2, FANCJ, and BRCA1. Co-treatment of TTFields with cisplatin or pemetrexed augmented efficacy versus each treatment alone, with the TTFields-pemetrexed combination displaying an additive effect, and the co-administration of TTFields with cisplatin demonstrating synergistic interaction. In vivo, tumor volume fold change was significantly decreased for the combination of TTFields with chemotherapy (cisplatin + pemetrexed) versus control, while levels of DNA damage within the tumor were increased.
    CONCLUSION: Efficacy of TTFields for the treatment of MPM is associated with increased DNA damage, elevated levels of DNA-damage related cell cycle arrest proteins, and reduced expression of FA pathway proteins. This latter effect may account for the synergistic interaction displayed for the TTFields-cisplatin combination, as cisplatin is known to cause DNA damage that requires the FA pathway for repair.
    DOI:  https://doi.org/10.1016/j.ijrobp.2021.07.1297
  9. BMC Cancer. 2021 Oct 26. 21(1): 1144
    Conspicuity of malignant pleural mesothelioma in contrast enhanced MDCT - arterial phase or late phase?
    Lukas Luerken, Philipp Laurin Thurn, Florian Zeman, Christian Stroszczynski, Okka Wilkea Hamer.
       BACKGROUND: To determine if late phase is superior to arterial phase intraindividually regarding conspicuity of MPM in contrast enhanced chest MDCT.
    METHODS: 28 patients with MPM were included in this retrospective study. For all patients, chest CT in standard arterial phase (scan delay ca. 35 s) and abdominal CT in portal venous phase (scan delay ca. 70 s) was performed. First, subjective analysis of tumor conspicuity was done independently by two radiologists. Second, objective analysis was done by measuring Hounsfield units (HU) in tumor lesions and in the surrounding tissue in identical locations in both phases. Differences of absolute HUs in tumor lesions between phases and differences of contrast (HU in lesion - HU in surrounding tissue) between phases were determined. HU measurements were compared using paired t-test for related samples. Potential confounding effects by different technical and epidemiological parameters between phases were evaluated performing a multiple regression analysis.
    RESULTS: Subjective analysis: In all 28 patients and for both readers conspicuity of MPM was better on late phase compared to arterial phase. Objective analysis: MPM showed a significantly higher absolute HU in late phase (75.4 vs 56.7 HU, p < 0.001). Contrast to surrounding tissue was also significantly higher in late phase (difference of contrast between phases 18.5 HU, SD 10.6 HU, p < 0.001). Multiple regression analysis revealed contrast phase and tube voltage to be the only significant independent predictors for tumor contrast.
    CONCLUSIONS: In contrast enhanced chest-MDCT for MPM late phase scanning seems to provide better conspicuity and higher contrast to surrounding tissue compared to standard arterial phase scans.
    Keywords:  Chest imaging; Contrast enhanced MDCT; Malignant pleural mesothelioma; Oncologic imaging; Retrospective study
    DOI:  https://doi.org/10.1186/s12885-021-08842-0
  10. Zhonghua Nei Ke Za Zhi. 2021 Nov 01. 60(11): 1002-1004
    [Recommendations for the management of malignant pleural mesothelioma].
    Y Y Chen, Y H Zhang, H Z Shi.
      
    DOI:  https://doi.org/10.3760/cma.j.cn112138-20210814-00555
  11. Int J Radiat Oncol Biol Phys. 2021 Nov 01. pii: S0360-3016(21)01463-2. [Epub ahead of print]111(3S): e144
    Segmentation of the Upper Torso for Lung Cancer TTFields Treatment Planning.
    O Peles, H Ben Atya, R Shamir, B Berger, Z Bomzon.
       PURPOSE/OBJECTIVE(S): Tumor Treating Fields (TTFields) is an FDA-approved treatment for glioblastoma multiforme (GBM) and malignant pleural mesothelioma (MPM). Moreover, TTFields therapy is currently investigated in a phase III clinical trial for the treatment of advanced Non-Small Cell Lung Cancer (NSCLC). Recent studies have shown that larger TTFields dose was associated with longer patients' survival. Therefore, personalized simulations to estimate the dose are performed as part of the patient treatment planning. For MPM and NSCLC treatment, these simulations require the segmentation of all upper torso tissues. A manual segmentation of the torso requires a few dozens of hours per patient and is impractical. Therefore, we have developed a computational method for semi-automatic segmentation of all upper torso tissues that are relevant to TTFields treatment planning.
    MATERIALS/METHODS: We have incorporated a dataset of 40 CT images of NSCLC patients that underwent TTFields treatment in the lungs for this study. We have utilized threshold-based methods combined with morphological operations, region growing methods and known anatomical spatial relations to automatically identify and segment the lungs, bones, skin, muscle, fat, spinal cavity, costal cartilage, trachea and bronchi. Other structures such as the heart, blood vessels, liver, stomach, spleen, esophagus, diaphragm and intervertebral discs were semi-automatically segmented by using a few reference points that were provided by a human rater. Since there is no gold standard segmentation of the whole torso, an experienced radiation oncologist that is highly familiar with TTFields treatment inspected the results of the algorithm on top of the original CT images.
    RESULTS: The radiation oncologist has confirmed that the semi-automatic segmentation of the torso provides an adequate quality result for TTFields treatment planning for all cases. The segmentation time was reduced to one hour on a typical patient, compared to 20 hours that is the estimated time required for a fully manual segmentation.
    CONCLUSION: We have presented a method for adequate quality segmentation of the upper torso in a reasonable time to facilitate TTFields treatment planning. In addition, this method facilitates the creation of a dataset for the development of state-of-the-art segmentation methods that utilize deep learning methods.
    DOI:  https://doi.org/10.1016/j.ijrobp.2021.07.593
  12. Int J Radiat Oncol Biol Phys. 2021 Nov 01. pii: S0360-3016(21)01457-7. [Epub ahead of print]111(3S): e142
    Creating Computational Models for Planning TTFields Treatment for Tumors in the Infratentorial Brain.
    Y Glozman, R Faran, R Shamir, B Berger, Z Bomzon.
       PURPOSE/OBJECTIVE(S): Tumor Treating Fields (TTFields) is an FDA-approved treatment for glioblastoma multiforme (GBM) and malignant pleural mesothelioma (MPM), and is currently being investigated in a phase III trial for the treatment of brain metastases from non-small cell lung cancer (NSCLC). Increased TTFields dose density at the tumor is associated with longer patient survival. Therefore, estimating dose at the tumor utilizing computational simulations with patient-specific computational models are integral for treatment planning. NSCLC brain metastases are often observed in infratentorial brain regions. In these cases, TTFields arrays may be placed on the head, neck, and upper back. Manual segmentation of this large area is impractical and time consuming. Therefore, we developed a computational method for semi-automatic segmentation of infratentorial tissues relevant to TTFields treatment planning.
    MATERIALS/METHODS: We incorporated a dataset of 20 head T1w Gad MRIs of patients treated with TTFields with segmentation of the infratentorial area, and 20 CT images that incorporate head, neck and upper torso from a public database for segmentation of extracranial structures. For the segmentation of the infratentorial zone we developed an atlas-based method that deforms a predefined statistical atlas to best fit the patient's MRI. Our method then revises the initial fitting to ensure the segmented structures adhere to known anatomical relations. For supratentorial brain areas, we incorporate a custom atlas-based method. Extra-cranial zones (head, neck and upper torso) were segmented with threshold-based methods for the skin, muscle, fat, bones, and bronchi. User-defined landmarks were used to segment the esophagus and the artery. The spine and CSF were segmented automatically by identifying the relevant area and defining a constant ratio between their diameters. To evaluate the segmentation of the infratentorial regions, a trained annotator manually segmented the infratentorial area of the 20 head MRIs. We compared manual and automatic segmentations and measured the Dice overlap score.
    RESULTS: The average Dice coefficient between the human annotator and the algorithms' segmentation was 0.84 (SD = 0.05) for cerebellum and 0.67 (SD = 0.05) for brainstem. These results are comparable to those observed in supratentorial regions with a method that was verified previously. The radiation oncologist confirmed that the semi-automatic segmentation of the infratentorial, and extracranial head, neck and upper torso provides a quality result for TTFields treatment planning in a reasonable amount of time for all cases. The infratentorial segmentation is fully automatic and typically lasts a few minutes. Segmentation of extracranial structures is semi-automatic and typically lasts less than an hour.
    CONCLUSION: We have developed a fast method for the segmentation of infratentorial structures for TTFields planning.
    DOI:  https://doi.org/10.1016/j.ijrobp.2021.07.587
  13. Int J Radiat Oncol Biol Phys. 2021 Nov 01. pii: S0360-3016(21)01462-0. [Epub ahead of print]111(3S): e144
    Treating Spinal-Cord Tumors with TTFields - A Simulation Study.
    A Naveh, T Marciano, Z Bomzon, D Divlianska, K Jaeckle.
       PURPOSE/OBJECTIVE(S): Tumor Treating Fields (TTFields) are an anti-mitotic non-invasive therapy approved for the treatment of certain solid tumors such as glioblastoma (GBM) and malignant pleural mesothelioma (MPM). TTFields are low intensity electrical fields in the medium frequency range (100-500 kHz). TTFields are applied to the patient using two pairs of transducer arrays (TAs) placed on the patient skin. The therapeutic threshold for treatment is considered to be 1 V/cm. The distribution of the electric field within the body is determined by the geometry of the arrays, the anatomical area being treated, and the electric parameters of the different tissues, specifically their electrical conductivity. Treatment planning is necessary to maximize the efficacy of the treatment. However, some regions of the body are more challenging to treat with TTFields due to their geometrical characteristics. One such example is the spinal cord. The spinal cord is an elongated structure with high electric conductivity encompassed within relatively electrically insulating bone structure of the spine. This results in a cable-like structure. The unique structure of the spine makes delivering TTFields to spinal tumors a non-trivial task. While the electric fields can propagate well along the spinal cord, they cannot easily penetrate the vertebrae to reach the spinal cord. In this study, we used simulations to establish ground rules for treating the spinal cord. Specifically, we tested the feasibility of using TTFields for treating leptomeningeal metastases of breast cancer.
    MATERIALS/METHODS: A realistic computational full body model of a healthy female was used in the study. Virtual transducer arrays were placed on the model's back at different heights, to the left and right of the spine. Arrays were also placed on the head and hips of the model. To simulate the delivery of TTFields to the spinal cord and CSF, we used Sim4Life v6.0 (ZMT Zürich) Ohmic-quasi-static solver. We applied 1A current at 150 kHz to the virtual arrays. In each simulation, we paired one array on the left to one array on the right, with different heights. The resulting field distribution along the spinal cord, CSF and nerves was then extracted.
    RESULTS: The field distribution has been analyzed along the axial plane of the patient. The mean field value for every slice was calculated, and the resulting axial-distribution was compared to the location of the two arrays along the models back. The results show that the maximal slice-averaged field intensity in the spinal cord is obtained between the arrays and in most cases is above the required 1 V/cm.
    CONCLUSION: This work demonstrates that by orthogonally positioning the two pairs of arrays on the patient back to surround the tumor area, it may be possible to provide sufficient field intensity to tumors within the CSF or of the spinal cord.
    DOI:  https://doi.org/10.1016/j.ijrobp.2021.07.592
  14. Int J Radiat Oncol Biol Phys. 2021 Nov 01. pii: S0360-3016(21)01709-0. [Epub ahead of print]111(3S): e252
    Activated Phosphoinositide 3-Kinase/AKT/mTOR Signaling Confers Resistance to Tumor Treating Fields (TTFields).
    A Klein-Goldberg, T Voloshin, E Zemer-Tov, R Paz, L Koren, K Wainer-Katsir, A Volodin, B Koltun, B Brant, M Giladi, U Weinberg, Y Palti.
       PURPOSE/OBJECTIVE(S): Tumor Treating Fields (TTFields) therapy is a clinically applied loco-regional, non-invasive, anti-mitotic treatment modality delivering to the tumor low intensity (1-3 V/cm) alternating electric fields (100-300 kHz). While TTFields therapy has demonstrated proven efficacy in management of glioblastoma and malignant pleural mesothelioma, tumor recurrence still occurs in some patients. In order to anticipate potential molecular mechanisms of resistance to TTFields, we developed TTFields-resistant cancer cell lines, and analyzed the changes in their signaling pathways. We also examined the in vitro efficacy of TTFields when combined with agents targeting the molecular candidates that possibly confer resistance to TTFields.
    MATERIALS/METHODS: To evaluate the mechanisms of cellular resistance to TTFields, we developed resistant ovarian (A2780), glioma (U-87-MG), and non-small cell lung carcinoma (H1299) cancer cell lines through continued long-term application of TTFields (one or two weeks, depending on the cell line), without treatment breaks. We then assessed the concomitant changes in cellular signaling pathways using an immunoassay followed by Western blot analysis. Finally, we characterized the mechanism of resistance by examining the in vitro efficacy of continued long-term application of TTFields in combination with pharmacological inhibitors including a PI3K/mTOR dual inhibitor (BGT226), and Pan- and isoform-specific inhibitors of PI3K (alpelisib, pictilisib, and BKM120), using cell count, apoptosis, and colony formation assays.
    RESULTS: Continued long-term application of TTFields resulted in reduced sensitivity to TTFields in all tested cell lines. Immunoassay and Western blot analysis showed significant activation of the PI3K/AKT/mTOR signaling pathway in response to TTFields treatment. The combination therapy of TTFields with either alpelisib, pictilisib, BKM120 or BGT226, inhibited AKT S473 phosphorylation and sensitized cancer cells to "long-term" TTFields application.
    CONCLUSION: Our study demonstrates that the PI3K/ AKT/ mTOR signaling pathway confers resistance to TTFields. This provides a rationale for the combined targeting of PI3K in patients treated with TTFields.
    DOI:  https://doi.org/10.1016/j.ijrobp.2021.07.839
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