Mesothelioma affects mostly older individuals who have been occupationally exposed to asbestos. The global mesothelioma incidence and mortality rates are unknown, because data are not available from ...developing countries that continue to use large amounts of asbestos. The incidence rate of mesothelioma has decreased in Australia, the United States, and Western Europe, where the use of asbestos was banned or strictly regulated in the 1970s and 1980s, demonstrating the value of these preventive measures. However, in these same countries, the overall number of deaths from mesothelioma has not decreased as the size of the population and the percentage of old people have increased. Moreover, hotspots of mesothelioma may occur when carcinogenic fibers that are present in the environment are disturbed as rural areas are being developed. Novel immunohistochemical and molecular markers have improved the accuracy of diagnosis; however, about 14% (high‐resource countries) to 50% (developing countries) of mesothelioma diagnoses are incorrect, resulting in inadequate treatment and complicating epidemiological studies. The discovery that germline BRCA1‐asssociated protein 1 (BAP1) mutations cause mesothelioma and other cancers (BAP1 cancer syndrome) elucidated some of the key pathogenic mechanisms, and treatments targeting these molecular mechanisms and/or modulating the immune response are being tested. The role of surgery in pleural mesothelioma is controversial as it is difficult to predict who will benefit from aggressive management, even when local therapies are added to existing or novel systemic treatments. Treatment outcomes are improving, however, for peritoneal mesothelioma. Multidisciplinary international collaboration will be necessary to improve prevention, early detection, and treatment.
Summary Background Despite recent advances in the treatment of advanced non-small-cell lung cancer, there remains a need for effective treatments for progressive disease. We assessed the efficacy of ...pembrolizumab for patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer. Methods We did this randomised, open-label, phase 2/3 study at 202 academic medical centres in 24 countries. Patients with previously treated non-small-cell lung cancer with PD-L1 expression on at least 1% of tumour cells were randomly assigned (1:1:1) in blocks of six per stratum with an interactive voice-response system to receive pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m2 every 3 weeks. The primary endpoints were overall survival and progression-free survival both in the total population and in patients with PD-L1 expression on at least 50% of tumour cells. We used a threshold for significance of p<0·00825 (one-sided) for the analysis of overall survival and a threshold of p<0·001 for progression-free survival. This trial is registered at ClinicalTrials.gov , number NCT01905657. Findings Between Aug 28, 2013, and Feb 27, 2015, we enrolled 1034 patients: 345 allocated to pembrolizumab 2 mg/kg, 346 allocated to pembrolizumab 10 mg/kg, and 343 allocated to docetaxel. By Sept 30, 2015, 521 patients had died. In the total population, median overall survival was 10·4 months with pembrolizumab 2 mg/kg, 12·7 months with pembrolizumab 10 mg/kg, and 8·5 months with docetaxel. Overall survival was significantly longer for pembrolizumab 2 mg/kg versus docetaxel (hazard ratio HR 0·71, 95% CI 0·58–0·88; p=0·0008) and for pembrolizumab 10 mg/kg versus docetaxel (0·61, 0·49–0·75; p<0·0001). Median progression-free survival was 3·9 months with pembrolizumab 2 mg/kg, 4·0 months with pembrolizumab 10 mg/kg, and 4·0 months with docetaxel, with no significant difference for pembrolizumab 2 mg/kg versus docetaxel (0·88, 0·74–1·05; p=0·07) or for pembrolizumab 10 mg/kg versus docetaxel (HR 0·79, 95% CI 0·66–0·94; p=0·004). Among patients with at least 50% of tumour cells expressing PD-L1, overall survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 14·9 months vs 8·2 months; HR 0·54, 95% CI 0·38–0·77; p=0·0002) and with pembrolizumab 10 mg/kg than with docetaxel (17·3 months vs 8·2 months; 0·50, 0·36–0·70; p<0·0001). Likewise, for this patient population, progression-free survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 5·0 months vs 4·1 months; HR 0·59, 95% CI 0·44–0·78; p=0·0001) and with pembrolizumab 10 mg/kg than with docetaxel (5·2 months vs 4·1 months; 0·59, 0·45–0·78; p<0·0001). Grade 3–5 treatment-related adverse events were less common with pembrolizumab than with docetaxel (43 13% of 339 patients given 2 mg/kg, 55 16% of 343 given 10 mg/kg, and 109 35% of 309 given docetaxel). Interpretation Pembrolizumab prolongs overall survival and has a favourable benefit-to-risk profile in patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer. These data establish pembrolizumab as a new treatment option for this population and validate the use of PD-L1 selection. Funding Merck & Co.
Single-drug checkpoint inhibition has shown efficacy in patients with recurrent malignant pleural mesothelioma. Here, we assessed the safety and efficacy of the combination of nivolumab, an ...anti-programmed cell death 1 antibody, plus ipilimumab, an anti-cytotoxic T-lymphocyte protein 4 antibody, in patients with previously treated and relapsed malignant pleural mesothelioma.
INITIATE was a prospective single-centre, single arm, phase 2 trial. Patients with malignant pleural mesothelioma who progressed after at least one line of platinum-containing chemotherapy were enrolled. Key eligibility criteria were measurable disease according to the modified Response Evaluation Criteria in Solid Tumours for mesotheliomas, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate organ function. Patients received intravenous nivolumab (240 mg every 2 weeks) plus intravenous ipilimumab (1 mg/kg every 6 weeks up to four times). Treatment was continued for up to 2 years or until confirmed progression or unacceptable toxicity. The primary endpoint was disease control at 12 weeks. All patients who received at least one dose of therapy were included in safety analysis and all patients who received one dose of therapy and at least one radiological assessment were included in the primary analysis. This trial is registered at ClinicalTrials.gov, number NCT03048474.
Between Oct 5, 2016, and Aug 3, 2017, 38 patients were enrolled in the study, of which two patients were excluded because they were not eligible for a biopsy. Of 36 eligible patients, one deteriorated before the start of the study so was not included in any analyses and one withdrew consent after one treatment cycle before radiological assessment so was included in the safety population only. 34 patients were evaluable for response assessment at 12 weeks. Of these, ten (29%) patients had a partial response and 13 (38%) patients had stable disease; thus, disease control was achieved by 23 (68%, 95% CI 50-83) of 34 patients. Treatment-related adverse events were reported in 33 (94%) patients. The most common adverse events were infusion-related reactions, skin disorders, and fatigue. Grade 3 treatment-related adverse events were reported in 12 (34%) of 35 patients.
In this single-centre phase 2 trial, the combination of nivolumab plus ipilimumab showed marked efficacy in patients with recurrent malignant pleural mesothelioma. The safety profile was consistent with known data on the combination regimen. Our results warrant further investigation of this combination in a phase 3 trial.
Bristol-Myers Squibb.
The M component and TNM stage groupings for malignant pleural mesothelioma (MPM) have been empirical. The International Association for the Study of Lung Cancer developed a multinational database to ...propose evidence-based revisions for the eighth edition of the TNM classification of MPM.
Data from 29 centers were submitted either electronically or by transfer of existing institutional databases. The M component as it currently stands was validated by confirming sufficient discrimination (by Kaplan-Meier analysis) with respect to overall survival (OS) between the clinical M0 (cM0) and cM1 categories. Candidate stage groups were developed by using a recursive partitioning and amalgamation algorithm applied to all cM0 cases.
Of 3519 submitted cases, 2414 were analyzable and 84 were cM1 cases. Median OS for cM1 cases was 9.7 months versus 13.4 months (p = 0.0013) for the locally advanced (T4 or N3) cM0 cases, supporting inclusion of only cM1 in the stage IV group. Exploratory analyses suggest a possible difference in OS for single- versus multiple-site cM1 cases. A recursive partitioning and amalgamation–generated survival tree on the OS outcomes restricted to cM0 cases with the newly proposed (eighth edition) T and N components indicates that optimal stage groupings for the eighth edition will be as follows: stage IA (T1N0), stage IB (T2–3N0), stage II (T1–2N1), stage IIIA (T3N1), stage IIIB (T1–3N2 or any T4), and stage IV (any M1).
This first evidence-based revision of the TNM classification for MPM leads to substantial changes in the T and N components and the stage groupings.
Molecular and immunologic breakthroughs are transforming the management of thoracic cancer, although advances have not been as marked for malignant pleural mesothelioma where pathologic diagnosis has ...been essentially limited to three histologic subtypes.
A multidisciplinary group (pathologists, molecular biologists, surgeons, radiologists, and oncologists), sponsored by European Network for Rare Adult Solid Cancers/International Association for the Study of Lung Cancer, met in 2018 to critically review the current classification.
Recommendations include: (1) classification should be updated to include architectural patterns and stromal and cytologic features that refine prognostication; (2) subject to data accrual, malignant mesothelioma in situ could be an additional category; (3) grading of epithelioid malignant pleural mesotheliomas should be routinely undertaken; (4) favorable/unfavorable histologic characteristics should be routinely reported; (5) clinically relevant molecular data (programmed death ligand 1, BRCA 1 associated protein 1 BAP1, and cyclin dependent kinase inhibitor 2A) should be incorporated into reports, if undertaken; (6) other molecular data should be accrued as part of future trials; (7) resection specimens (i.e., extended pleurectomy/decortication and extrapleural pneumonectomy) should be pathologically staged with smaller specimens being clinically staged; (8) ideally, at least three separate areas should be sampled from the pleural cavity, including areas of interest identified on pre-surgical imaging; (9) image-acquisition protocols/imaging terminology should be standardized to aid research/refine clinical staging; (10) multidisciplinary tumor boards should include pathologists to ensure appropriate treatment options are considered; (11) all histologic subtypes should be considered potential candidates for chemotherapy; (12) patients with sarcomatoid or biphasic mesothelioma should not be excluded from first-line clinical trials unless there is a compelling reason; (13) tumor subtyping should be further assessed in relation to duration of response to immunotherapy; and (14) systematic screening of all patients for germline mutations is not recommended, in the absence of a family history suspicious for BAP1 syndrome.
These multidisciplinary recommendations for pathology classification and application will allow more informative pathologic reporting and potential risk stratification, to support clinical practice, research investigation and clinical trials.
The only registered systemic treatment for malignant pleural mesothelioma (MPM) is platinum based chemotherapy combined with pemetrexed, with or without bevacizumab. Immunotherapy did seem active in ...small phase II trials. In this review, we will highlight the most important immunotherapy-based research performed and put a focus on the future of MPM. PD-(L)1 inhibitors show response rates between 10 and 29% in phase II trials, with a wide range in progression free (PFS) and overall survival (OS). However, single agent pembrolizumab was not superior to chemotherapy (gemcitabine or vinorelbine) in the recent published PROMISE-Meso trial in pre-treated patients. In small studies with CTLA-4 inhibitors there is evidence for response in some patients, but it fails to show a better PFS and OS compared to best supportive care in a randomized study. A combination of PD-(L)1 inhibitor with CTLA-4 inhibitor seem to have a similar response as PD-(L)1 monotherapy. The first results of combining durvalumab (PD-L1 blocking) with cisplatin-pemetrexed in the first line are promising. Another immune treatment is Dendritic Cell (DC) immunotherapy, which is recently tested in mesothelioma, shows remarkable anti-tumor activity in three clinical studies. The value of single agent checkpoint inhibitors is limited in MPM. There is an urgent need for biomarkers to select the optimal candidates for immunotherapy among MPM patients in terms of efficacy and tolerance. Results of combination checkpoint inhibitors with chemotherapy are awaiting.
Photodynamic Therapy in Oncology Triesscheijn, Martijn; Baas, Paul; Schellens, Jan H. M. ...
The oncologist (Dayton, Ohio),
October 2006, Letnik:
11, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Learning Objectives
After completing this course, the reader will be able to:
Discuss the safety and side effects of PDT.
Identify appropriate indications for PDT.
Explain the choice of PDT over ...other treatment modalities.
Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com
Photodynamic therapy (PDT) is increasingly being recognized as an attractive, alternative treatment modality for superficial cancer. Treatment consists of two relatively simple procedures: the administration of a photosensitive drug and illumination of the tumor to activate the drug. Efficacy is high for small superficial tumors and, except for temporary skin photosensitization, there are no long‐term side effects if appropriate protocols are followed. Healing occurs with little or no scarring and the procedure can be repeated without cumulative toxicity. Considering the efficacy and lack of long‐term toxicity of PDT, and the fact that the first treatment of cancer with PDT was done more than 100 years ago, one might expect that this treatment had already become an established therapy. However, PDT is currently offered in only a few selected centers, although it is slowly gaining acceptance as an alternative to conventional cancer therapies. Here, we show the developmental steps PDT underwent and summarize the current clinical applications. The data show that, when properly used, PDT is an effective alternative treatment option in oncology.
Summary Background Vorinostat is a histone deacetylase inhibitor that changes gene expression and protein activity. On the basis of the clinical benefit reported in patients with malignant pleural ...mesothelioma treated in a phase 1 study of vorinostat, we designed this phase 3 trial to investigate whether vorinostat given as a second-line or third-line therapy improved patients' overall survival. Methods This double-blind, randomised, placebo-controlled trial was done in 90 international centres. Patients with measurable advanced malignant pleural mesothelioma and disease progression after one or two previous systemic regimens were eligible. After stratification for Karnofsky performance status, histology, and number of previous chemotherapy regimens, patients were randomly assigned (1:1) by use of an interactive voice response system with a block size of four to either treatment with vorinostat or placebo. Patients received oral vorinostat 300 mg (or matching placebo) twice daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 of a 21-day cycle. The primary endpoints were overall survival and safety and tolerability of vorinostat. The primary efficacy comparison was done in the intention-to-treat population, and safety and tolerability was assessed in the treated population. This trial is registered with ClinicalTrials.gov , number NCT00128102. Findings From July 12, 2005, to Feb 14, 2011, 661 patients were enrolled and randomly assigned to receive either vorinostat (n=329) or placebo (n=332) and included in the intention-to-treat analysis. Median overall survival for vorinostat was 30·7 weeks (95% CI 26·7–36·1) versus 27·1 weeks (23·1–31·9) for placebo (hazard ratio 0·98, 95% CI 0·83–1·17, p=0·86). The most common grade 3 or worse adverse events for patients treated with vorinostat were fatigue or malaise (51 16% patients in the vorinostat group vs 25 8% in the placebo group) and dyspnoea (35 11% vs 45 14%). Interpretation In this randomised trial, vorinostat given as a second-line or third-line therapy did not improve overall survival and cannot be recommended as a therapy for patients with advanced malignant pleural mesothelioma. Funding Merck & Co, Inc.
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