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T. Nakano
Moderator of
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SC06 - Novel Therapies in Malignant Pleural Mesothelioma and Thymic Malignancies (ID 330)
- Event: WCLC 2016
- Type: Science Session
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 4
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SC06.01 - Comprehensive Genomic Analysis of Malignant Pleural Mesothelioma (ID 6621)
14:30 - 14:50 | Author(s): R. Bueno
- Abstract
- Presentation
Abstract not provided
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SC06.02 - Stratified Therapy for Malignant Pleural Mesothelioma (ID 6622)
14:50 - 15:10 | Author(s): D.A. Fennell
- Abstract
- Presentation
Abstract not provided
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SC06.03 - Intraoperative Therapies in Malignant Pleural Mesothelioma (ID 6623)
15:10 - 15:30 | Author(s): I. Opitz
- Abstract
- Presentation
Abstract:
Intraoperative Therapies in Malignant Pleural Mesothelioma The rational of localized / intracavitary treatment is to eliminate microscopic residual disease (MRD) after macroscopic complete resection (MCR) for mesothelioma patients. The advantage of the treatment is that local effects can be enhanced whereas systemic side effects of the therapeutic agents applied might be reduced. Several approaches have been investigated over the past decades in preclinical and clinical trials, such as intracavitary chemotherapy (iCTX), immunotherapy (iIT), photodynamic therapy (PDT) and gene therapy (iGT). Intracavitary chemotherapy (iCTX) iCTX has been studied after mesothelioma resection, not only after extrapleural pneumonectomy (EPP) but also after (extended) pleurectomy/decortication ((e)P/D). The main therapeutic agent used is cisplatin. In some trials hyperthermia was additionally added with the aims to enhance the penetration of cisplatin into tissues and maximize its cytotoxicity in tumor cells [1]. Hyperthermic intrapleural perfusion had a maximum tolerated dose of 225-250 mg Cisplatin/m[2] BSA [2]. The morbidity ranges from 13 to 85% and the mortality from 0 to 29% [2, 3]. Some complications are related to renal toxicity which was the dose limiting adverse event [2]. Median survival time reaches up to 35.3 months in low-risk MPM patients receiving hyperthermic intraplueral cisplatin chemotherapy following MCR [4]. This treatment is only considered for well-designed clinical trials. In vivo preclinical model using intrapleural administration of cisplatin-mixed loaded to a fibrin carrier improved the local drug concentration and prolonged the exposure of tissue to high cisplatin concentration [5]. Our phase I dose escalation trial (INFLuenCe – Meso; see figure) has proven the safety of this treatment approach (manuscript in preparation). This treatment regimen is now being tested in a phase II trial (NCT01644994). Figure 1 In addition to chemotherapy, other substances have also been tested for intracavitary treatment. Recently, Tada, et. al. reported study plan for a phase I trial for intrapleural treatment with zoledronic acid, a third generation of bisphosphonates, in inoperable MPM, after having successfully proven the efficacy of zoledronic in a pre-clinical model [6]. Intracavitary immunotherapy (iIT) MPM is not a classical “immunogenic” tumor. Intrapleural instillation of cytokines such as interleukin (IL)-2, interferon (IFN)-α and IFN-γ provided a good control of malignant pleural effusion (MPE) and MPM with minimal toxicity [7, 8]. To prolong and increase local exposure of IFNs, recent studies implemented immuno-gene therapy approach using adenoviral vector expressing human IFNs. Four out of 10 patients with MPM and metastatic pleural effusions showed stable disease following a single dose of intrapleural adenoviral vector expressing IFN-β [9]. Nevertheless due to rapid production of neutralizing antibody against adenovirus, no improvement of gene transfer efficacy was achieved after the second dose [10]. The same research group conducted a clinical trial assessing the safety of adenoviral-mediated IFN-α2b in combination with chemotherapy. Recent data from this trial showed that the treatment is well tolerated and 25% of patients had partial response [11]. An intrapleural treament with re-directed T cells genetically engineered to express chimeric antigen receptor (CAR) that specifically recognizes tumor antigens is an attractive therapeutic option. A clinical phase I trial for intrapleural administration of fibroblast activation protein (FAP)-specific re-directed T cells is currently being conducted (NCT01722149). Photodynamic therapy (PDT) PDT is a light based cancer therapy. Most modern PDT applications involve three key components: a photosensitizer, a light source and tissue oxygen. The photosensitizing agent accumulates in tumor cells and is activated by light of a specific wavelength to produce reactive singlet oxygen that mediates cellular toxicity. The tumor cells are killed through both apoptosis and necrosis and by damaging tumor vasculature. It may also induce inflammatory reaction capable of stimulating a tumor directed host immune response. The advantages of this treatment are that its efficacy is not influenced by chemo- or radio-resistance of tumor cells, that it can be repeated at the same site without compromising its efficacy and that it does not compromise the ability to administer other treatment modalities in patients with recurrent or residual disease. PDT should be combined with macroscopic complete resection due to limited depth of penetration. Localized inflammation and fluid accumulation after treatment can modestly extend hospital stay. PDT appears promising and may improve local control and potentially prolong survival in properly selected patients who are able to undergo MCR, with clinical outcomes appearing best when PDT is combined with lung-sparing definitive surgery [12]. Friedberg reported a median survival of 31.7 months (41.2 months in patients with epithelioid histological subtype), but the progression free survival was only 9.6 months [13]. Intracavitary gene therapy (iGT) Gene therapy is based upon transfer of genetic material, including complementary DNA, full-lengths genes, small interfering RNA or oligonucleotids into cells for therapeutic purposes. For sufficient gene delivery, adenovirus is the most widely used in clinical trials among a variety of viral and non-viral vectors. In addition to delivering cytokine expressing vectors or re-directed T cells (see iIT part), several different cancer gene therapy approaches are currently used including the so called suicide gene therapy wherein a neoplasm is transduced with a cDNA encoding for an enzyme rendering tumor cells sensitive to a benign agent by converting the product to a toxic metabolite. The Herpes Simplex Virus 1- thymidine kinase (HSVtk) gene encodes for an enzyme that converts ganciclovir, an antiviral drug, to its cytotoxic metabolite. Intrapleural adenovirus HSVtk/ganciclovir administration was safe in MPM and two patients survived >6.5 years. Nevertheless, due to the fact that transgenes HSVtk were only detected at the surface of tumor tissues, the authors suggested that the treatment efficacy may be a result of antitumor immune response stimulation [14]. MPM tumor genome is characterized by frequent mutations in tumor suppressor genes such NF2, BAP1 or p53, thus the delivery of tumor suppressor gene expressing vectors into tumor cells can serve as an attractive treatment approach. The delivery of adenovirus expressing p53 has been tested in clinical trials for lung cancer but did not show better clinical benefit over chemotherapy [15]. This may be due to limited transfection efficiency of the vector and the stimulation of neutralizing antibody, therefore an improvement of transfection is still needed for the further development of gene therapy. References: 1. Sugarbaker, P.H., et al., Update on chemotherapeutic agents utilized for perioperative intraperitoneal chemotherapy. Oncologist, 2005. 10(2): p. 112-22. 2. Richards, W.G., et al., Phase I to II Study of Pleurectomy/Decortication and Intraoperative Intracavitary Hyperthermic Cisplatin Lavage for Mesothelioma. J Clin Oncol, 2006. 24(10): p. 1561-1567. 3. de Bree, E., et al., Cytoreductive surgery and intraoperative hyperthermic intrathoracic chemotherapy in patients with malignant pleural mesothelioma or pleural metastases of thymoma. Chest, 2002. 121(2): p. 480-7. 4. Sugarbaker, D.J., et al., Hyperthermic intraoperative pleural cisplatin chemotherapy extends interval to recurrence and survival among low-risk patients with malignant pleural mesothelioma undergoing surgical macroscopic complete resection. J Thorac Cardiovasc Surg, 2013. 145(4): p. 955-63. 5. Lardinois, D., et al., Intrapleural topical application of cisplatin with the surgical carrier Vivostat increases the local drug concentration in an immune-competent rat model with malignant pleuromesothelioma. J Thorac Cardiovasc Surg, 2006. 131(3): p. 697-703. 6. Tada, Y., et al., An intrapleural administration of zoledronic acid for inoperable malignant mesothelioma patients: a phase I clinical study protocol. Springerplus, 2016. 5: p. 195. 7. Astoul, P., et al., Intrapleural recombinant IL-2 in passive immunotherapy for malignant pleural effusion. Chest, 1993. 103(1): p. 209-13. 8. Antoniou, K.M., E. Ferdoutsis, and D. Bouros, Interferons and their application in the diseases of the lung. Chest, 2003. 123(1): p. 209-16. 9. Sterman, D.H., et al., A phase I clinical trial of single-dose intrapleural IFN-beta gene transfer for malignant pleural mesothelioma and metastatic pleural effusions: high rate of antitumor immune responses. Clin Cancer Res, 2007. 13(15 Pt 1): p. 4456-66. 10. Sterman, D.H., et al., A phase I trial of repeated intrapleural adenoviral-mediated interferon-beta gene transfer for mesothelioma and metastatic pleural effusions. Mol Ther, 2010. 18(4): p. 852-60. 11. Sterman, D.H., et al., Pilot and Feasibility Trial Evaluating Immuno-Gene Therapy of Malignant Mesothelioma Using Intrapleural Delivery of Adenovirus-IFNalpha Combined with Chemotherapy. Clin Cancer Res, 2016. 22(15): p. 3791-800. 12. Simone, C.B., 2nd and K.A. Cengel, Photodynamic therapy for lung cancer and malignant pleural mesothelioma. Semin Oncol, 2014. 41(6): p. 820-30. 13. Friedberg, J.S., et al., Radical pleurectomy and intraoperative photodynamic therapy for malignant pleural mesothelioma. Ann Thorac Surg, 2012. 93(5): p. 1658-65; discussion 1665-7. 14. Sterman, D.H., et al., Long-term Follow-up of Patients with Malignant Pleural Mesothelioma Receiving High-Dose Adenovirus Herpes Simplex Thymidine Kinase/Ganciclovir Suicide Gene Therapy. Clin Cancer Res, 2005. 11(20): p. 7444-7453. 15. Schuler, M., et al., Adenovirus-mediated wild-type p53 gene transfer in patients receiving chemotherapy for advanced non-small-cell lung cancer: results of a multicenter phase II study. J Clin Oncol, 2001. 19(6): p. 1750-8.
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SC06.04 - Immunotherapy of Malignant Pleural Mesothelioma and Thymic Malignancies: The End of the Beginning? (ID 6624)
15:30 - 15:45 | Author(s): J.P. Van Meerbeeck
- Abstract
- Presentation
Abstract:
The significant improvement in outcome observed with immune checkpoint inhibitors in advanced melanoma and NSCLC have triggered their use in mesothelioma and thymic tumours. Both tumours are characterized by an unmet need to improve their prognosis and an immunosuppressive environment induced by (i) the (over-)expression of checkpoint receptors, responsible for controlling and inactivating the immune system in order to avoid autoimmunity and prevent collateral tissue damage- and (ii) by a silencing of the antigen presenting function of dendritic cells by tumor-derived soluble factors, leading to a defective induction of cytotoxic T–lymphocytes response [1]. The new paradigm consists of reactivating these silenced immune responses by either monoclonal antibodies or cell-based therapies. CTLA-4 is responsible for modulating central T-cell activation in the lymph nodes. Under physiological conditions, the immune inhibitory effect of CTLA-4 is involved in provoking an effective immune response without causing excessive damage to the normal surrounding tissue. However, tumor cells can stimulate abnormal expression of CTLA-4 by secreting TGF-beta, that induces CTLA-4 overexpression, resulting in a state of T-cell dysfunction whereby T-cells fail to proliferate and are no longer able to exert their effector functions. Tremelimumab and ipilimumab are selective monoclonal antibodies against CTL-A4 and block its binding to CD80 and CD 86, thereby enhancing T cell activity and anti tumor immunity. There are no known predictive factors for anti-CTL-A4 therapy in mesothelioma. After 2 phase 2 trials at different dose levels –which were negative for their primary endpoint, but nevertheless considered promising- DETERMINE compared tremelimumab to placebo as second line treatment in MPM [2]. No difference in outcome was reported, but an increased class specific toxicity in the patients treated with tremelimumab. The PD-1-PD-L1 axis is responsible for controlling peripheral T-cell activation at the tumor site. Overexpression of PD-L1 is thought to induce immune tolerance. In MPM, PD-L1 expression by immunohistochemistry was reported in 20-70% of formalin-fixed paraffin embedded mesothelioma, in 70% of thymic carcinomas and in 23% of thymomas [1,3]. In mesothelioma, PD-L1 expression overexpression is more common in non-epitheloid histology, is associated with a significantly worse survival. PD-L1 expression is furthermore considered a –weak- predictive factor for the activity of immune checkpoint inhibitors in NSCLC, besides mutagenic load and the formation of neo-epitopes. Several anti PD-(L)1 antibodies are registered and/or in development for use in other tumour types. Promising phase 2 trial results in mostly pretreated mesothelioma patients are summarized in the table [4-6]. Expression level of PD-L1 did not correlate with response in either trial.Checkpoint inhibitors in mesothelioma
Dendritic cells (DC), obtained by leukapheresis, can be loaded with synthetic peptides coding for parts of tumor-associated antigens, a lysate of tumor material of the patient itself (autologous dendritic cell-therapy) or with other sources of tumor-specific antigens (allogeneic dendritic cell-therapy). Wilms' tumor 1 (WT1) is an ideal candidate for a tumor selective cancer vaccine in cancers expressing WT1, such as MPM. Two vaccines have investigated this approach. Vaccination with autologous DC’s, electroporated with mRNA encoding the WT1 antigen was evaluated in 10 patients with mesothelioma not progressing after platinum/ pemetrexed-based chemotherapy [7]. Biweekly intradermal vaccinations were administered for an intended period of 6 months, followed by monthly or bimonthly injections. DC vaccination was well-tolerated: no systemic toxicity was recorded; local reactions at the injections sites occurred in all patients, but were mild and self-limiting. At a median follow-up of 22.7 months, 6 patients are alive, 4 have died and 1 year survival rate is 90% from start of treatment, suggesting that adjuvant DC-based immunotherapy provides a clinical benefit. In a pilot trial in pretreated MPM, the multivalent native and synthetic WT1 peptide vaccine Galinpepimut-S was well-tolerated and CD4/8 immune responses were generated. After completing multimodality therapy, 40 mesothelioma patients were randomized to receive maintenance Montanide and GM-CSF with or without Galinpepimut-S [8]. There were no serious treatment related adverse events. Based on a pre-specified futility analysis, accrual was stopped. Median PFS from randomization was 11.4 months in the experimental arm vs. 5.7 months in the control arm (HR 0.69). Similarly, median overall survival (OS) from randomization was 21.4 months in the Galinpepimut-S arm vs. 16.6 months in the control arm (HR 0.52). In the subgroup with R0 resection, median OS was 39.3 months in the Galinpepimut-S and 24.8 in the control arm (p = 0.04). A confirmatory adequately powered randomized adjuvant study is awaited. In the European DENIM trial, patients not progressing after 1[st] line platinum-pemetrexed chemotherapy will be randomized between standard follow up and a maintenance treatment consisting of 5 injections of DC’s, pulsed with an allogeneic lysate obtained from 5 well-characterized clinical grade human malignant mesothelioma cell lines. Cell-based immunotherapy carries high expectations but remains cumbersome and labour-intensive. Anti-CTL-A4 antibody-based immunotherapy in mesothelioma has so far failed to deliver the expected improvement in outcome. Whether this also applies to anti-PD-(L)1 monoclonal antibodies remains to be seen from ongoing and future trials. A low mutational burden and the limited formation of neo-epitopes under chemotherapy, -both considered important predictive factors for immune checkpoint therapy- are the challenges for this approach. As in other tumour types, studying a combination of different checkpoint inhibitors either with or without chemotherapy or with anti-angiogenic agents is of interest [9]. In thymic tumours, the presence or risk of developing immune-mediated paraneoplastic syndromes is of particular concern. This could be an argument to prioritize checkpoint inhibitors in thymic carcinomas[10]. References 1: Marcq E et al. Targeting immune checkpoints: new opportunity for mesothelioma treatment? Cancer Treatm Rev 2015; 41(10):914 2:Kindler HL et al.. Tremelimumab as second- or third-line treatment of unresectable malignant mesothelioma (MM): Results from the global, double-blind, placebo-controlled DETERMINE study. J Clin Oncol 2016; 34 (suppl): abstr 8502 3: Katsuya Y et al. Immunohistochemical status of PD-L1 in thymoma and thymic carcinoma. Lung Cancer. 2015;88(2):154 4: Alley EW et al. Single-Agent Pembrolizumab for Patients with Malignant Pleural Mesothelioma. J Thorac Oncol 2015; 10(9) supplement 2: abstr O11.03 5: Quispel-Janssen J et al. NIVOLUMAB IN MALIGNANT PLEURAL MESOTHELIOMA (NIVOMES): AN INTERIM ANALYSIS. Proc IMiG 13, Birmingham 2016; abstr MS 04.07 6: Hassan R et al. Avelumab in patients with advanced unresectable mesothelioma from the JAVELIN solid tumor phase Ib trial: safety, clinical activity and PD-L1 expression. J Clin Oncol 2016; 34(suppl): abstr 8503 7: Berneman ZN et al. Dendritic cell vaccination in malignant pleural mesothelioma: A phase I/II study. J Clin Oncol 2014; 32:5s: abstr 7583 8: Zauderer MG et al. Randomized phase II study of adjuvant WT1 vaccine (SLS-001) for malignant pleural mesothelioma after multimodality therapy. J Clin Oncol 2016; 34 (suppl): abstr 8519 9: Anonymous. Nivolumab Monotherapy or Nivolumab Plus Ipilimumab, for Unresectable Malignant Pleural Mesothelioma (MPM) Patients (MAPS2). Available at: https://clinicaltrials.gov/ct2/show/NCT02716272 10: Anonymous. MK-3475 in Patients With Thymic Carcinoma. Available at: https://clinicaltrials.gov/ct2/show/NCT02364076Trial Drug Phase Line N Subtype ORR/DCR (%) PFS DETERMINE (2) Tremelimumab 3 2/3 382 Ep: 83% 4.5/31.7 2.8 m KEYNOTE 28 (4) Pembrolizumab 2 2 25 all PDL1+ 28/76 49.4% @ 6m NIVOMES (5) Nivolumab 2 NR 18 NR 27/49 NR JAVELIN (6) Avelumab 1b 2-5 53 Ep: 83% 9.4/56.6 17.1 w
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Author of
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P3.03 - Poster Session with Presenters Present (ID 473)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 3
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.03-003 - Mesothelium Covering Pleural Plaque Is Not Primarily Involved in Asbestos-Induced Mesothelial Carcinogenesis in Human (ID 5638)
14:30 - 14:30 | Author(s): T. Nakano
- Abstract
Background:
Malignant pleural mesothelioma (MPM) initially arises not from the visceral pleura but parietal pleural mesothelial cells in the thoracic cavity. MPM has a close relationship to asbestos exposure in etiology. The carcinogenic potential of asbestos fibers has been linked to their geometry, size, and chemical composition. Long respirable fibers(length>5μm, diameter<3μm) have an increased potential to cause mesothelioma. Asbestos also induces non-neoplastic diseases of the pleura. Pleural plaques are thought to be formed by lymphatic transport of short asbestos fibers from lung parenchyma to lymphatic stomata in the parietal pleura, with the fibers undergoing phagocytosis by macrophages in the submesothelial layer to synthesize collagen. Long fibers are lodged and retained at these stomata orifices to lead to asbestos carcinogenesis. Plaques, almost always, are produced in the parietal pleura, of which surface is covered with a single mesothelial cell layer. In this study, we evaluated whether mesothelium covering pleural plaque was primarily involved in asbestos-induced mesothelial carcinogenesis in human.
Methods:
40 patients with MPM were received a medical thoracoscopy with narrow band imaging(NBI) and autofluorescence imaging(AFI), in addition to white light under local anaesthesia. 10 patients were T1, and 8 were T2 clinical stage. All patients had a free thoracic cavity with pleural effusion. 40/32（80％）patients had a history of asbestos exposure(ex. 20 occupational exposure, 7 environmental exposure, 5 none).
Results:
Small nodules of mesothelioma and plaques were present simultaneously on the parietal pleura in 15 MPM patients. NBI could depict the blood vessels on parietal pleural surface more clearly than white light. T1 tumors changed in color to Brown with NBI, and to magenta with AFI. Plaques were usually sharply demarcated from surrounding the parietal pleura, and were avascular and raised hard yellow to white lesions. Individual plaques were smooth surfaced or composed of small rounded knobs. Small nodules of T1 tumors were visualized on the parietal pleura except for the surface of pleural plaques, where neo-vascularization was clearly demonstrated with NBI. With progress of the clinical stage of MPM(T1⇒T2), implanted small nodule came to be seen on the surface of pleural plaque with AFI and NBI.
Conclusion:
Thoracoscopical examination for early clinical stage of MPM shows that the origin of MPM is the mesothelial cells in the parietal pleura, and that mesothelium covering on the surface of pleural plaque was not primarily involved in asbestos-induced mesothelial carcinogenesis in human.
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P3.03-016 - Association between the Stainability of the Neurofibromatosis Type 2 Gene-Related Protein Merlin and the Tumor Properties of Mesotheliomas (ID 5680)
14:30 - 14:30 | Author(s): T. Nakano
- Abstract
Background:
Mutations in the genes cyclin-dependent kinase inhibitor 2A (CDKN2A), BRCA-1 associated protein 1 (BAP1), and neurofibromatosis type 2 (NF2) are observed in malignant pleural mesothelioma (MPM). We observed biallelic BAP1 alterations in 61% of MPMs and found that mutations are particularly frequent in epithelioid-type malignant mesotheliomas (Cancer Sci, 103:868-74, 2012). In addition, Loss-of-function mutations in NF2 are relatively frequent (40%) in MPMs have indicated. Merlin is a tumor suppressor protein coded by NF2; both merlin and the ezrin/radixin/moesin proteins are associated with suppression of invasion and metastasis of tumor cells. In this study, we examined the association between stainability of merlin and the tumor properties of MPM.
Methods:
Following definitive histological diagnoses of 35 cases of MPM (epithelial: n=31, biphasic: n=2, desmoplastic: n=2), we conducted immunohistochemical staining for merlin in thin sections of paraffin-embedded tumor tissue. Stainability was assessed with H-scores. The clinical stage of MPM was defined at the time near the tumor tissue harvesting time; the association between the clinical stage and therapeutic outcomes was assessed based on the outcomes of first-line chemotherapy with cisplatin (CDDP) or carboplatin(CBDCA) plus pemetrexed (PEM). The anti-merlin antibody used was LS-B394 (LSBio, Seattle, Washington, USA).
Results:
1) Seven MPMs (20%) were negative or weakly positive for merlin (H-score 0-30); of these seven MPMs, one was desmoplastic, while six were epithelial. Six MPMs were strongly positive for merlin (H-score ≥250); all six of these MPMs were epithelial. 2) No difference in merlin stainability was observed between epithelial (n=31) and non-epithelial (n=4) MPMs. Similarly, on examination of the association between stainability and IMIG staging, no differences in stainability were observed between stages 1 to 4. 3) No differences in stainability were observed between the first-line chemotherapy partial response group and progressive disease group.
Conclusion:
Loss-of-function mutations in the tumor suppressor gene NF2 lead to enhanced expression of focal adhesion kinase; although these mutations are demonstrated in decreased normal expression of the tumor suppressor protein merlin, no trend was observed in the morphological differentiation patterns of MPM. In addition, although the ratio of cells with high aldehyde dehydrogenase enzymatic activity is increased by CDDP/PEM treatment, we observed no association between CDDP/PEM sensitivity and merlin stainability. The association between NF2/merlin and tumor properties must be studied in more cases.
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P3.03-032 - PET/CT for Patients with Very Early Clinical Stage of Malignant Pleural Mesothelioma: When Can PET/CT Detect Tumor Growth of T0/T1a Mesothelioma? (ID 5725)
14:30 - 14:30 | Author(s): T. Nakano
- Abstract
Background:
Positron Emission Tomography/Computed Tomography (PET/CT) is well recognized as an important modality to detect malignant neoplasm, which plays a crucial role in the assessment of patients with malignant pleural mesothelioma (MPM). T1a category of IMIG classification refers to an early tumor that involves the parietal pleura only. And, there are a certain number of patients with more earlier clinical stage than T1a, i.e., radiological and thoracoscopical T0 stage. Those patients with T0 stage have neither visible pleural tumor nor pathologic PET/CT findings, and they are sometimes misdiagnosed as nonspecific pleuritis after a complete investigation including thoracoscopical biopsies. Those patients will turn out to be malignant during follow-up period. The purpose of this study was to investigate when tumor growth came to be detectable with PET/CT in patients with very early clinical stage of MPM whose PET/CT had been negative.
Methods:
Seven histologically-proven MPM patients with T0/T1a clinical stage were followed up with PET/CT (Epithelioid/unknown;6/1). A surgical thoracoscopy(VATS) or medical thoracoscopy with narrow band and autofluorescence imaging in addition to white light had been performed to obtain adequate materials of pleura and to diagnose T1-stage macroscopically. No patients had received talc pleurodesis. The initial thoracic CT scans showed pleural effusion without thickening of pleura, and all of the initial PET/CT evaluation was negative. The radiological examinations, including PET/CT and contrast and/or plain CT for loco-regional disease were reviewed to see tumor growth that came to be able to detect with PET scan. Interpretation of positive PET scan for malignancy is SUV>2.5.
Results:
The median interval between the initial PET/CT and the follow-up PET scan to come to identify malignant nodules for the first time was 32 months (5 - 46 months). Two patients with epithelioid and unknown MPM showed a positive finding of PET scan at the site of pleural intervention (thoracoscopy/thoracentesis), of which interval were 5 and 8 months, respectively. PET-positive pleural nodules, 5.1 ～ 8.2 mm in diameter, were demonstrated in 4 patients. And, a diffuse pleural thickening with positive PET scan, 6.5 mm in thickness, was shown in 1 patient with epithelioid MPM.
Conclusion:
PET/CT is a valuable modality for detecting the progression of T0/T1a tumors > 5 mm in diameter. Interval between PET-negative T0/T1a tumor and PET-positive tumor growth is more than 2 years (median; 32 months), and tumor seeding at the site of previous pleural intervention is an early manifestation of MPM.
