Current treatment landscape for oligometastatic non-small cell lung cancer

Non-small cell lung cancer; OligometastaticCáncer de pulmón de células no pequeñas; OligometastásicoCàncer de pulmó de cèl·lules no petites; OligometastàticThe management of patients with advanced non-small cell lung carcinoma (NSCLC) has undergone major changes in recent years. On the one hand, improved sensitivity of diagnostic tests, both radiological and endoscopic, has altered the way patients are staged. On the other hand, the arrival of new drugs with antitumoral activity, such as targeted therapies or immunotherapy, has changed the prognosis of patients, improving disease control and prolonging survival. Finally, the development of radiotherapy and surgical and interventional radiology techniques means that radical ablative treatments can be performed on metastases in any location in the body. All of these advances have impacted the treatment of patients with advanced lung cancer, especially in a subgroup of these patients in which all of these treatment modalities converge. This poses a challenge for physicians who must decide upon the best treatment strategy for each patient, without solid evidence for one optimal mode of treatment in this patient population. The aim of this article is to review, from a practical and multidisciplinary perspective, published evidence on the management of oligometastatic NSCLC patients. We evaluate the different alternatives for radical ablative treatments, the role of primary tumor resection or radiation, the impact of systemic treatments, and the therapeutic sequence. In short, the present document aims to provide clinicians with a practical guide for the treatment of oligometastatic patients in routine clinical practice

Impact of SARS-CoV-2 Infection on Patients with Cancer: Retrospective and Transversal Studies in Spanish Population

[EN] Background: Studies of patients with cancer affected by coronavirus disease 2019 (COVID-19) are needed to assess the impact of the disease in this sensitive population, and the influence of different cancer treatments on the COVID-19 infection and seroconversion. Material and Methods: We performed a retrospective analysis of all patients hospitalized with RT-PCR positive for COVID-19 in our region to assess the prevalence of cancer patients and describe their characteristics and evolution (Cohort 1). Concurrently, a transversal study was carried out in patients on active systemic cancer treatment for symptomatology and seroprevalence (IgG/IgM by ELISA-method) against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) (Cohort 2). Results: A total of 215 patients (Cohort 1) were admitted to hospital with a confirmed COVID-19 infection between February 28 and April 30, 2020, and 17 died (7.9%). A medical record of cancer was noted in 43 cases (20%), 6 of them required Intensive care unit ICU attention (14%), and 7 died (16%). There were thirty-six patients (83%) who tested IgG/IgM positive for SARS-CoV-2. Patients on immunosuppressive therapies presented a lower ratio of seroconversion (40% vs. 8%; p = 0.02). In Cohort 2, 166 patients were included in a symptoms-survey and tested for SARS-CoV-2. Any type of potential COVID-19-related symptom was referred up to 67.4% of patients (85.9% vs. 48.2% vs. 73.9%, for patients on chemotherapy, immunotherapy and targeted therapies respectively, p < 0.05). The seroprevalence ratio was 1.8% for the whole cohort with no significant differences by patient or treatment characteristics. Conclusion: Patients with cancer present higher risks for hospital needs for COVID-19 infection. The lack of SARS-CoV-2 seroconversion may be a concern for patients on immunosuppressive therapies. Patients receiving systematic therapies relayed a high rate of potentially COVID-19-related symptoms, particularly those receiving chemotherapy. However, the seroconversion rate remains low and in the range of general population.We thank all the patients who consented to this study, and the frontline healthcare professionals who are involved in patients' care during this pandemic. We also thank the technical assistants: M. Portero Hernandez, A. Real Perez, and M. Ocasar Garcia. VGB's research work is partially supported by the Ministerio de Ciencia e Innovacion of Spain under grant No. PID2019-110442GB-I00.Garde-Noguera, J.; Fernández-Murga, ML.; Giner-Bosch, V.; Domínguez-Márquez, V.; García Sánchez, J.; Soler-Cataluña, JJ.; López Chuliá, F.... (2020). Impact of SARS-CoV-2 Infection on Patients with Cancer: Retrospective and Transversal Studies in Spanish Population. Cancers. 12(12):1-11. https://doi.org/10.3390/cancers12123513S1111212Munster, V. 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The Lancet, 395(10241), 1907-1918. doi:10.1016/s0140-6736(20)31187-9Zhang, L., Zhu, F., Xie, L., Wang, C., Wang, J., Chen, R., … Zhou, M. (2020). Clinical characteristics of COVID-19-infected cancer patients: a retrospective case study in three hospitals within Wuhan, China. Annals of Oncology, 31(7), 894-901. doi:10.1016/j.annonc.2020.03.296Winter, A. K., & Hegde, S. T. (2020). The important role of serology for COVID-19 control. The Lancet Infectious Diseases, 20(7), 758-759. doi:10.1016/s1473-3099(20)30322-4Venkatesulu, B. P., Thoguluva Chandrasekar, V., Giridhar, P., Advani, P., Sharma, A., Hsieh, C. E., … Krishnan, S. (2020). A systematic review and meta-analysis of cancer patients affected by a novel coronavirus. doi:10.1101/2020.05.27.20115303Van Assen, S., Holvast, A., Benne, C. A., Posthumus, M. D., van Leeuwen, M. A., Voskuyl, A. E., … Bijl, M. (2010). Humoral responses after influenza vaccination are severely reduced in patients with rheumatoid arthritis treated with rituximab. Arthritis & Rheumatism, 62(1), 75-81. doi:10.1002/art.25033Rousseau, B., Loulergue, P., Mir, O., Krivine, A., Kotti, S., Viel, E., … Tournigand, C. (2012). Immunogenicity and safety of the influenza A H1N1v 2009 vaccine in cancer patients treated with cytotoxic chemotherapy and/or targeted therapy: the VACANCE study. Annals of Oncology, 23(2), 450-457. doi:10.1093/annonc/mdr141Di Cosimo, S., Malfettone, A., Pérez-García, J. M., Llombart-Cussac, A., Miceli, R., Curigliano, G., & Cortés, J. (2020). Immune checkpoint inhibitors: a physiology-driven approach to the treatment of coronavirus disease 2019. European Journal of Cancer, 135, 62-65. doi:10.1016/j.ejca.2020.05.026Bersanelli, M., Scala, S., Affanni, P., Veronesi, L., Colucci, M. E., Banna, G. L., … Liotta, F. (2020). Immunological insights on influenza infection and vaccination during immune checkpoint blockade in cancer patients. Immunotherapy, 12(2), 105-110. doi:10.2217/imt-2019-0200Pollán, M., Pérez-Gómez, B., Pastor-Barriuso, R., Oteo, J., Hernán, M. A., Pérez-Olmeda, M., … Fernández de Larrea, N. (2020). Prevalence of SARS-CoV-2 in Spain (ENE-COVID): a nationwide, population-based seroepidemiological study. The Lancet, 396(10250), 535-544. doi:10.1016/s0140-6736(20)31483-5Choe, P. G., Perera, R. A. P. M., Park, W. B., Song, K.-H., Bang, J. H., Kim, E. S., … Oh, M. (2017). MERS-CoV Antibody Responses 1 Year after Symptom Onset, South Korea, 2015. Emerging Infectious Diseases, 23(7), 1079-1084. doi:10.3201/eid2307.170310Cao, W.-C., Liu, W., Zhang, P.-H., Zhang, F., & Richardus, J. H. (2007). Disappearance of Antibodies to SARS-Associated Coronavirus after Recovery. 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Inclusion of non-inferiority analysis in superiority-based clinical trials with single-arm, two-stage Simon's design

Non-inferiority (NI) analysis is not usually considered in the early phases of clinical development. In some negative phase II trials, a post-hoc NI analysis justified additional phase III trials that were successful. However, the risk of false positive achievements was not controlled in these early phase analyses. We propose to preplan NI analyses in superiority-based Simon's two-stage designs to control type I and II error rates. Simulations have been proposed to assess the control of type I and II errors rates with this method. A total of 12,768 two-stage Simon's design trials were constructed based on different assumptions of rejection response probability, desired response probability, type I and II errors, and NI margins. P-value and type II error were calculated with stochastic ordering using Uniformly Minimum Variance Unbiased Estimator. Type I and II errors were simulated using the Monte Carlo method. The agreement between calculated and simulated values was analyzed with Bland-Altman plots. We observed the same level of agreement between calculated and simulated type I and II errors from both two-stage Simon's superiority designs and designs in which NI analysis was allowed. Different examples has been proposed to explain the utility of this method. Inclusion of NI analysis in superiority-based single-arm clinical trials may be useful for weighing additional factors such as safety, pharmacokinetics, pharmacodynamic, and biomarker data while assessing early efficacy. Implementation of this strategy can be achieved through simple adaptations to existing designs for one-arm phase II clinical trials

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Análisis inmunohistoquímico de mediadores moleculares implicados en angiogénesis LDH5 y VEGFR2/pKDR en pacientes con cáncer colorrectal avanzado: determinación de su valor como biomarcadores

Tema. El esquema de tratamiento de primera línea estándar más utlizado para los pacientes diagnosticados de adenocarcinoma colorectal avanzado es en la actualidad la combinación de Oxaliplatino, Fluoropirimidinas y Bevacizumab. No todos los pacientes se benefician de igual manera, siendo necesarios identificar marcadores moleculares capaces de predecir el pronóstico y la posibilidad de respuesta. Objetivos. El objetivo de nuestro estudio es determinar el papel pronóstico y predictivo de la expresión inmunohistoquímica de dos proteínas implicadas en la angiogénesis y adaptación metabólica a la hipoxia tumoral: LDH5 y VEGFR/pKDR, en pacientes tratados con Oxaliplatino y Fluoropirimidinas con o sin Bevacizumab. Como objetivos secundarios pretendemos analizar el valor pronóstico de las mutaciones de RAS en estos pacientes, así como su valor predictivo de respuesta en pacientes tratados con fármacos antiangiogénicos, y realizar un análisis de las características clínico-patológicas asociadas con peor pronóstico en estos pacientes. Metodología. Estudio retrospectivo de la cohorte de pacientes diagnosticados de CCR avanzado y tratados con combinación de quimioterapia con Fluoropirimidinas, y Oxaliplatino, asociados o no a Bevacizumab en cuatro hospitales de la Comunidad Valenciana. Se analizarán la expresión inmunohistoquímica de las proteínas VEGFR/pKDR y LDH5, así como la presencia de mutaciones en la vía RAS (KRAS y NRAS), y estudiaremos la correlación que pudiera existir entre la sobreexpresión de dichas proteínas o la presencia de dichas mutaciones con el pronóstico de los pacientes y la eficacia del tratamiento recibido. Para el análisis inmunohistoquímico se realizó una matriz de tejido con bloques de tumor representativos de cada paciente, utilizándose el anticuerpo anti-pKDR 34a, y el anticuerpo anti-LDH5 Abcam-9002, y se analizaron utilizando un sistema de clasificación semicuantitativa. Para el objetivo secundario del estudio en el que se pretende analizar la importancia de las mutaciones de la familia RAS como marcador pronóstico en CCR avanzado, se llevó a cabo un análisis de genotipificación de las muestras. Resultados Encontramos un total de 112 pacientes que cumplían los criterios de inclusión del estudio en nuestras bases de datos. Todos los pacientes fueron diagnosticados de CCR avanzado entre enero de 2010 y diciembre de 2013 y fueron tratados con un esquema de quimioterapia que incluía Fluoropirimidinas y Oxaliplatino (XELOX o FOLFOX) con o sin bevacizumab. El análisis Inmunohistoquímico fue valorable en 84 pacientes para pKDR (75%) y en 87 pacientes para LDH5 (77,6%). Siete pacientes (8,3%) presentaban expresión leve o indetectable; mientras que los 77 restantes (91,7%) presentaban expresión moderada o intensa. Dieciséis pacientes (18,3%) presentaban baja expresión; mientras setenta y un pacientes (81,7%) mostraron una fuerte expresión de LDH 5. 93 pacientes con material histológico disponible para el análisis de N-RAS y K-RAS. Cuarenta y nueve pacientes (52,6%) presentaban tumores con mutaciones de RAS, 47 mutaciones de K-RAS y 2 de N-RAS. La baja expresión de VEGFR/pKDR se asoció con mayor tasa de respuesta (100% vs 46,3%, p= 0,019), así como con una tendencia favorable pero no significativa en términos de SG (28 vs 22 meses, p= 0.09) y SLP (15 vs 12 meses, p=0,4); La baja expresión de LDH5 no se asoció con características clínicas de mejor pronóstico, y tampoco se asocia con una mayor tasa de respuesta (56,2 vs 60,8%, p= 0.47), ni con una mejor SG (20 vs 24 meses, p= 0.17) ni SLP (11 vs 12 meses, p= 0.28). El estado mutacional de RAS no se asoció con un peor pronóstico (SG; RASmut 20 meses vs RASwt 24 meses, p= 0,63), y fue predictivo de la respuesta al tratamiento (TR RASmut 48,9% vs RASwt 59,9%, p= 0.12). La Carcinomatosis Peritoneal y la afectación multiorgánica al diagnóstico de pacientes con CCR avanzado son factores pronósticos que se relacionan independientemente con peor SG y peor SLP. Conclusiones La sobreexpresión inmunohistoquímica de VEGFR/pKDR y LDH5 se observa en un alto porcentaje de pacientes con CCR avanzado. No hemos observado diferencias significativas en la supervivencia global o la supervivencia libre de progresión de estos pacientes en función de la expresión dichos marcadores moleculares

Stereotactic body radiation therapy: A good dance partner of oligometastatic non-small cell lung cancer to the sound of SINDAS study

The European Organization for Research on Treatment of Cancer Research published a consensus statement to establish the key criteria to define oligometastatic disease (OMD). According to those criteria, all lesions (both primary and metastatic) should be amenable to radical intent treatment with acceptable toxicity. Several retrospective studies have shown that adding local ablative therapy to the treatment of OMD improves outcomes; however, due to the diverse selection criteria and treatment strategies used in those studies, it is difficult to compare directly results to draw definitive conclusions. In recent years, prospective phase II trials, such as the SABR-COMET and "Oligomez" trials, have shown that stereotactic body radiation therapy (SBRT) improves outcomes in patients with OMD. More recently, interim results of the randomised phase 3 SINDAS trial were reported at the annual meeting of the American Society of Clinical Oncology 2020 demonstrating that upfront SBRT added to systemic treatment with tyrosine kinase inhibitors yielded a significant benefit in both progression-free survival and overall survival in patients with epidermal growth factor receptor-mutant oligometastatic non-small cell lung cancer. In the present editorial, we review the definition and historical context of advanced non-small cell lung cancer with OMD. In addition, we review the scientific evidence for local ablative therapy and SBRT and discuss the results of recently published prospective studies. We also discuss in depth the results of the SINDAS study, including the strengths and weaknesses of the study and the barriers to extrapolating these results to routine clinical practice.Sin financiaciónNo data JCR 2020No data SJR 2020No data IDR 2020UE

Inclusion of non-inferiority analysis in superiority-based clinical trials with single-arm, two-stage Simon's design

No inferioridad; Fase II; Brazo únicoNo inferioritat; Fase II; Braç únicNon-inferiority; Phase II; Single-armIntroduction: Non-inferiority (NI) analysis is not usually considered in the early phases of clinical development. In some negative phase II trials, a post-hoc NI analysis justified additional phase III trials that were successful. However, the risk of false positive achievements was not controlled in these early phase analyses. We propose to preplan NI analyses in superiority-based Simon’s two-stage designs to control type I and II error rates. Methods: Simulations have been proposed to assess the control of type I and II errors rates with this method. A total of 12,768 two-stage Simon’s design trials were constructed based on different assumptions of rejection response probability, desired response probability, type I and II errors, and NI margins. P-value and type II error were calculated with stochastic ordering using Uniformly Minimum Variance Unbiased Estimator. Type I and II errors were simulated using the Monte Carlo method. The agreement between calculated and simulated values was analyzed with Bland-Altman plots. Results: We observed the same level of agreement between calculated and simulated type I and II errors from both two-stage Simon’s superiority designs and designs in which NI analysis was allowed. Different examples has been proposed to explain the utility of this method. Conclusion: Inclusion of NI analysis in superiority-based single-arm clinical trials may be useful for weighing additional factors such as safety, pharmacokinetics, pharmacodynamic, and biomarker data while assessing early efficacy. Implementation of this strategy can be achieved through simple adaptations to existing designs for onearm phase II clinical trialsJavier Cortés has received consulting and advisor fees from: Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo and Erytech. In addition, Javier Cortés has received honorarias from: Roche, Novartis, Celgene, Eisai, Pfizer and Samsung. Add more, Javier Cortés has received research funding fees to the institution from Roche. Finally, Javier Cortés has stock options, patents and intellectual property from MedSIR

Soluble Biomarkers with Prognostic and Predictive Value in Advanced Non-Small Cell Lung Cancer Treated with Immunotherapy

Numerous targeted therapies have been evaluated for the treatment of non-small cell lung cancer (NSCLC). To date, however, only a few agents have shown promising results. Recent advances in cancer immunotherapy, most notably immune checkpoint inhibitors (ICI), have transformed the treatment scenario for these patients. Although some patients respond well to ICIs, many patients do not benefit from ICIs, leading to disease progression and/or immune-related adverse events. New biomarkers capable of reliably predicting response to ICIs are urgently needed to improve patient selection. Currently available biomarkers—including programmed death protein 1 (PD-1) and its ligand (PD-L1), and tumor mutational burden (TMB)—have major limitations. At present, no well-validated, reliable biomarkers are available. Ideally, these biomarkers would be obtained through less invasive methods such as plasma determination or liquid biopsy. In the present review, we describe recent advances in the development of novel soluble biomarkers (e.g., circulating immune cells, TMB, circulating tumor cells, circulating tumor DNA, soluble factor PD-L1, tumor necrosis factor, etc.) for patients with NSCLC treated with ICIs. We also describe the potential use of these biomarkers as prognostic indicators of treatment response and toxicity

Deep diving in the PACIFIC: Practical issues in stage III non-small cell lung cancer to avoid shipwreck

After publication of the PACIFIC trial results, immune checkpoint inhibitor-based immunotherapy was included in the treatment algorithm of locally advanced non-small cell lung cancer (NSCLC). The PACIFIC trial demonstrated that 12 mo of durvalumab consolidation therapy after radical-intent platinum doublet chemotherapy with concomitant radiotherapy improved both progression-free survival and overall survival in patients with unresectable stage III NSCLC. This is the first treatment in decades to successfully improve survival in this clinical setting, with manageable toxicity and without deterioration in quality of life. The integration of durvalumab in the management of locally advanced NSCLC accentuates the need for multidisciplinary, coordinated decision-making among lung cancer specialists, bringing new challenges and controversies as well as important changes in clinical work routines. The aim of the present article is to review-from a practical, multidisciplinary perspective-the findings and implications of the PACIFIC trial. We evaluate the immunobiological basis of durvalumab as well as practical aspects related to programmed cell death ligand 1 determination. In addition, we comprehensively assess the efficacy and toxicity data from the PACIFIC trial and discuss the controversies and practical aspects of incorporating durvalumab into routine clinical practice. Finally, we discuss unresolved questions and future challenges. In short, the present document aims to provide clinicians with a practical guide for the application of the PACIFIC regimen in routine clinical practice.Sin financiaciónNo data 2020UE