Treatment strategies for locally advanced non-small cell lung cancer in elderly patients: Translating scientific evidence into clinical practice

https://doi.org/10.1016/j.critrevonc.2021.103378Get rights and content

Highlights

  • Current standard treatments for locally advanced NSCLC.

  • Focus on treatments for locally advanced NSCLC in elderly patients.

  • Main issues for multimodality approach in elderly patients.

Abstract

Treatment of locally advanced NSCLC (LA-NSCLC) is focused on multimodal strategy, including chemotherapy and radiotherapy (in combination or as alternative treatments), followed by surgery in selected cases. Recently, durvalumab consolidation after definitive chemo-radiation has shown a meaningful overall survival benefit. However, it is important to note that elderly patients represent a high proportion of NSCLC population and frailty and comorbidities can significantly limit treatment options. Indeed, elderly patients are under-represented in clinical trials and data to drive treatment selection in this category of patients are scanty. Available data, main issues and controversies on multimodal treatment in elderly LA-NSCLC patients will be reviewed in this paper.

Introduction

Locally advanced NSCLC (LA-NSCLC) is a heterogeneous disease including different clinical and radiological patterns. Primary tumor extension and nodal involvement define two main subgroups: potentially resectable and unresectable NSCLCs (Goldstraw et al., 2016). Hence, the aims in treating LA-NSCLC can be largely different among stage III patients, varying from the curative intent of induction treatment for potentially resectable disease to the palliative intent including controlling pain, respiratory and mediastinal symptoms (Postmus et al., 2017; Passiglia et al., 2020; Jazieh et al., 2021). Overall, it represents an evolving setting and recent introduction of immunotherapy has revolutionized the treatment approach for unresectable disease and underlined the importance of proper staging and multidisciplinary assessment. Several clinical trials are currently ongoing with the aim to further improve treatment strategies for LA-NSCLC (Table 1).

Integration of different treatments requires a complex multidisciplinary evaluation, taking into account disease extension and node involvement but also comorbidities and functional status. For clinical decision making about multimodal treatment, information stemming from different trials studying different treatment schedules are available. Multidisciplinary teams have essential role and should personalize treatment and consider toxicity risks of each treatment and further impact of multimodal strategy on tolerability.

Aim of the present manuscript is to review the results of the available clinical trials and to discuss the current challenges in the setting of LA-NSCLC with a focus on elderly population.

The possibility to achieve radical resection in LA-NSCLC depends on radiologic and pathological staging, including high resolution positron emission tomography (PET) scan, contrast enhanced brain computed tomography (CT) or magnetic resonance imaging (MRI), cardio-pulmonary function assessment and cytological or histological evaluation of mediastinal lymph nodes. LA-NSCLC is considered potentially resectable when staged as IIIA according to TNM VIII classification: either resectable T3-4 N0 or N1 at most, or T1-2 with a single station non-bulky N2 involvement (Postmus et al., 2017). The proper management of these cases should be discussed by a multidisciplinary team and includes induction chemotherapy or induction chemo-radiation followed by surgery in case of non-progressive disease (Postmus et al., 2017; Albain et al., 2009) (Fig. 1). When N2 involvement is unforeseen before primary surgery for T1-T3 disease, the post-surgical treatment includes adjuvant chemotherapy followed or not by radiotherapy (Postmus et al., 2017; Pignon et al., 2008).

As post-operative radiotherapy (PORT) is concerned, such treatment is not considered as mandatorily recommended for completely resected NSCLC with histologically proven N2 nodal involvement. In fact, the LungART phase III trial recently scaled back the role of PORT for stage IIIAN2 patients, as it did not have a statistically significant impact on their disease free survival (DFS), but negatively affects their overall survival (OS) rates due to treatment-related adverse events (Le Pechoux et al., 2020). Multidisciplinary case discussion is anyway encouraged, expecially in case of multi-station N2 involvement.

Stage IIIB and IIIC NSCLC are considered unresectable by definition, as well as stage IIIA with multilevel N2 involvement, bulky disease or unresectable T3-T4 due to local extension (Postmus et al., 2017). The management of unresectable LA-NSCLC is based on definitive chemo-radiation and concurrent schedules are preferred, when feasible (Postmus et al., 2017; Auperin et al., 2010) (Fig. 1, Fig. 2). For patients receiving definitive chemo-radiation, immunotherapy consolidation with durvalumab administered for 12 months has recently been approved. In Europe, durvalumab approval is limited to programmed death-ligand 1 (PD-L1) positive (≥1%) tumors (Antonia et al., 2018; Gray et al., 2019) (Fig. 2).

The definition of elderly population has been recently re-defined as a dynamic concept, taking into account functional and social status and comorbidities in addition to chronological age. Thus, though the elderly age cutoff was previously set at 65 years, biological age should be always considered when evaluating patients for cancer treatment (Anon., 2019; Forman et al., 1992). Indeed, as for the majority of cancer types, lung cancer incidence is higher in elderly than in younger patients, with a mean age of 70 years at diagnosis (AmericanCancerSociety, 2019).

As expected, when compared to younger patients, elderly patients have higher proportion of comorbidities and are more frequently Eastern Cooperative Oncology Group (ECOG) performance status (PS) equal or greater than 2 (Chouaid et al., 2017). Comorbidities, concomitant drugs and high ECOG PS are among the main exclusion criteria from clinical trials, thus the elderly population is typically under-represented in clinical trials.

This is particularly important in clinical trials for LA-NCSLC, often enrolling highly selected patients to be offered multimodal treatments including chemotherapy, radiotherapy and potentially surgical treatment with curative intent.

Physiologic changes occurring with ageing represent a major challenge for patients’ tolerance to treatments. As a matter of fact, the elderly experience a decrease in lean body mass associated with accumulation of fatty tissues in different organs, leading to organ senescence and subsequent impairment in organ function. In particular senescence affects their ability to sustain stressing conditions, as cancer treatments can be considered (Aspinall and Lang, 2018). Among the affected organs, a reduced bone marrow reserve is responsible for reduced capacity to face hematological toxicities. In addition, age affects drug metabolism. Specifically, adipose tissue increases the half-life of lipophilic drugs and decreases the one of soluble drugs. In the elderly, also hepatic and renal drug clearance may be significantly reduced due to intrinsic organ senescence and comorbidities affecting the circulatory system (Klotz, 2009). Moreover, the impact of cognitive disorders in patients increases with age (Repetto et al., 2002) and could significantly influence the management and the outcome of adverse events.

The concept of frailty, meaning a state of increased vulnerability for morbidity and/or mortality when exposed to a stressor, is becoming increasingly relevant when considering elderly population. Frailty probability increases with age but the concept is independent from chronological age and stems from multidisciplinary evaluation. Frail people are more vulnerable to the effects and adverse outcomes of potential stressors (Theou and Rockwood, 2012). As such, diverse geriatric scales have been developed to assess the complex health status of older adults and to screen for frailty so as to identify those patients at higher risk to develop adverse outcomes related to clinical interventions (Morley et al., 2013). Indeed, multi-dimensional geriatric assessment (GA) is commonly used in oncology to determine whether elderly patients with cancer are fit, vulnerable or frail, by assessing comorbidity, functional status, physical performance, nutritional status, polypharmacy, social support, cognition, and psychological status. Validated tools are available for specific contexts for geriatric assessment (Charlson Comorbidity Index, Activities of daily living, Mini-Mental State Examination, Mini Nutritional Assessment, Geriatric depression scale) (Korc-Grodzicki et al., 2015). The most used screening tools specifically designed for assessment of frailty in elderly patients with cancer are the G8 and the abbreviated comprehensive geriatric assessment (aCGA) (Korc-Grodzicki et al., 2015).

Section snippets

Surgery in the elderly: what is known?

The largest clinical trial evaluating the role of adding surgery to induction chemo-radiation in 396 stage IIIA (N2) patients had OS as primary endpoint (Albain et al., 2009). The study showed a DFS benefit (HR 0.77, 95 % CI 0.62−0.96, p = 0.017) in the investigational arm, but no OS benefit (HR 0.87, 95 % CI 0.70–1.10, p = 0.24). Patients receiving pneumonectomy had higher mortality rate, when compared to lobectomy. When translating the results into clinical practice, it is important to

Radiotherapy in the elderly: the challenge is open

In the past, radiotherapy alone was considered a valid option for the treatment of lung cancers not receiving surgery and patients older than 75 years were not excluded from this approach (Lonardi et al., 2000; Hayakawa et al., 2001)

A retrospective analysis including more than thousand lung cancer patients enrolled in six EORTC trials found no significant differences in OS and toxicity in patients treated with thoracic radiotherapy according to age (Pignon et al., 1998). Anyway, data on the

Chemotherapy in locally advanced disease and geriatric oncology

Platinum-based chemotherapy has a well-established role in the neoadjuvant or adjuvant treatment of resectable LA-NSCLC (Pignon et al., 2008; Burdett et al., 2014; Lim et al., 2009) (Fig. 2). Although both adjuvant and neoadjuvant treatments have been associated with an improved survival, the potential advantages of neoadjuvant treatment include a better tolerability and the possibility to avoid unnecessary surgery (Lim et al., 2009). In the LACE meta-analysis on adjuvant treatments for NSCLC,

Chemo-radiation strategies in elderly patients

In the context of unresectable LA-NSCLC, the first established standard of treatment was definitive radiotherapy. The first attempts to add chemotherapy were made in the 1990s and overall chemo-radiation demonstrated to add survival benefit to radiotherapy alone (5-year-OS rate 7% vs 5%) (Non-small Cell Lung Cancer Collaborative Group, 1995; Dillman et al., 1990) (Fig. 2). During the following years, several clinical trials have been conducted to evaluate different chemotherapy and radiotherapy

The emerging role of immunotherapy

The role of immunotherapy in LA-NSCLC has been defined very recently (Antonia et al., 2018). The PACIFIC study is a phase III trial evaluating the role of the anti-PD-L1 antibody durvalumab administration as consolidation treatment in patients with stage III NSCLC who had not progressed after concurrent platinum-based chemo-radiotherapy. Durvalumab maintenance for 12 months resulted in OS benefit compared to placebo: 36-month OS rate was 57 % in the durvalumab arms versus 43.5 % in the placebo

Conclusions and perspectives

Elderly NSCLC patients are under-represented in clinical trials, due to the higher incidence of comorbidities and poor performance status (Passaro et al., 2019; Pasello et al., 2020; Passaro et al., 2020). Few prospective data are available on this population of patients, while they represent

the majority of patients evaluated in clinical practice (Gridelli et al., 2018; Atagi et al., 2018).

In general, treatment-related toxicity increases according to age and this is even more evident when

Role of the funding source

The authors did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of Competing Interest

The authors report no declarations of interest.

Bonanno Laura, MD, is Medical Oncologist at the Division of Medical Oncology 2, Istituto Oncologico Veneto in Padova. In 2006 she graduated with full marks and in 2011 she achieved her Residency in Medical Oncology with full marks at the University of Padova. During her residency, she has also worked at Dexeus University Institute of Barcelona, under the supervision of Dr. Rosell, involved in a translational research project in lung cancer. She is now involved as principal investigator and

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  • Bonanno Laura, MD, is Medical Oncologist at the Division of Medical Oncology 2, Istituto Oncologico Veneto in Padova. In 2006 she graduated with full marks and in 2011 she achieved her Residency in Medical Oncology with full marks at the University of Padova. During her residency, she has also worked at Dexeus University Institute of Barcelona, under the supervision of Dr. Rosell, involved in a translational research project in lung cancer. She is now involved as principal investigator and coinvestigator in more than 40 clinical trials, both spontaneous and good clinical practice, concerning the treatment of lung cancer, malignant pleural mesothelioma and thymic tumors. She has achieved also molecular biology expertise and she is currently coordinating translational research projects in lung cancer. She is author or co-author of more than 50 papers has published in peer-reviewed journals, in the field of translational research and thoracic oncology. She is currently member of ASCO, European Society of Medical Oncology (ESMO), Italian Association of Medical Oncology (AIOM), International Association for the Study of Lung Cancer (IALSC) and European Thoracic Oncology Platform (ETOP).

    Ilaria Attili, MD, is Medical Oncologist at European Institute of Oncology, Milan, Italy. She received Degree in Medicine with honours and was awarded "excellent graduate" at Sapienza – University of Rome in 2013, and achieved her Residency in Medical Oncology with full marks at the University of Padova in 2020. During her residency, she has also worked at Dexeus University Institute of Barcelona, under the supervision of Dr. Rosell, involved in a translational research project in lung cancer. She is currently involved in several clinical trials exploring the personalized treatment for lung cancer, including target agents and immune-check point inhibitors. She has published original research articles and reviews in International Indexed journals, in the field of translational research and thoracic oncology. She is reviewer for several peer reviewed journals. She is currently a member of ESMO, AIOM, IALSC.

    Alberto Pavan, MD, is Medical Oncologist at Istituto Oncologico Veneto IOV, Padua. He received his MD Degree in Medicine with honours at Università degli Studi di Padova. He is involved in several clinical trials exploring the personalized treatment for lung cancer, including target agents and immune-check point inhibitors. He has published several original research articles and reviews in International Indexed journals, in the field of translational research and thoracic oncology. He is currently a member of ESMO and of AIOM.

    Matteo Sepulcri, MD, is a Radiation Oncologist currently working at the Radiotherapy Unit of the Veneto Institute of Oncology, Padua. He graduated in Medicine in 2011 at the University of Trieste then he moved to Padua where he started his residency in Radiation Oncology in 2013. As a resident, he has focused his studies in thoracic oncology and uro-oncology with a special interest in SBRT (Stereotactic Body Radiation Therapy). He attended a stage at the Institut Gustave Roussy, Villejuif - Paris, to gain expertise on radiation therapy for thoracic malignancies. In 2017 he specialized in Radiation Oncologist with honors. Since late 2017 he has been working in the field of thoracic radiotherapy in Padua, taking part in the Lung Unit program. His main work focus is modern radiotherapy and the interaction of SBRT with new systemic therapies, such as immune-checkpoint molecules and tyrosine-kinase inhibitors. He is now involved in several clinical trials on lung cancer, both for the early and advanced stages of the disease. He is currently member of the European Society of Radiation Oncology (ESTRO), Associazione Italiana di Radioterapia Oncologica (AIRO) and Società Italiana di Uro-Oncologia (SIUrO).

    Giulia Pasello is Medical Oncologist at the Division of Medical Oncology 2 at the Veneto Institute of Oncology (IOV) in Padua. She specialized in Medical Oncology in 2010 and received her PhD in Clinical and Experimental Sciences in 2015. Dr. Pasello is committed to medical treatment and clinical research of solid tumours, with particular interest in thoracic neoplasms. She is Coinvestigator and Principal Investigator in more than 40 clinical trials on Non-Small Cell Lung Cancer, Small Cell Lung Cancer, Malignant Pleural Mesothelioma and Thymic cancer. She is currently involved as Principal Investigator in basic and translational research projects on rare thoracic cancers, particularly on Malignant Pleural Mesothelioma and neuroendocrine tumors. She is author of about 40 papers in peer-reviewed journals, the majority on clinical and molecular features of thoracic cancers. She was the recipient of the 2010 European Society for Medical Oncology Translational Research Fellowship Award for her work on the Identification of novel molecular targets and biological agents for the chemotherapy of Malignant Pleural Mesothelioma. In 2015, she was recipient of My First AIRC Grant for the translational project MET-targeting in Small Cell Lung Cancer, currently ongoing. She is a reviewer for several peer reviewed journals focused on thoracic oncology.

    Federico Rea is Full Professor of Thoracic Surgery at the University of Padova, Italy, Director of the Thoracic Surgery Unit at the Univerity Hospital of Padova. He is also in charge of the Lung transplantation center of Padova. He specialized in Thoracic Surgery, worked with JD Cooper at Toronto General Hospital (Canada) and with G. Patterson at Barnes University Hospital of St. Louis (U.S.A.). Throughout his career, Prof. Rea has been involved in the surgical treatment of neoplastic diseases affecting the thoracic district. He performed over 4,000 major surgical procedures and over 200 lung transplantations as lead surgeon. He has published more than 200 papers in peer-reviewed journals.

    Valentina Guarneri is Associate Professor of Oncology at the University of Padua, and attending physician at the Division of Medical Oncology 2 at the Istituto Oncologico Veneto. She completed her fellowship in Oncology in 2003, and she obtained her PhD Degree in Clinical and Experimental Oncology in 2007. In 2005 she was appointed Assistant Professor of Oncology at the University of Modena and Reggio Emilia, where she also chaired the Breast Unit. In 2005, she also completed a 6-month-research experience at the Department of Breast Medical Oncology, UT. MD Anderson Cancer Center, Houston, Texas, where in 2009 she was Visiting Assistant Professor. In 2014 she was appointed Associate Professor of Oncology at the University of Padua. Prof Guarneri’s research interest is mainly focused on clinical and translational research for breast cancer patients. She has published more than 80 papers in peer-reviewed journals and has presented more than 100 lectures at national and International conferences. Prof Guarneri was member of the ESMO Young Oncologists committee and of the ESMO E-Learning and CME WG. She is currently member of the ESMO OncologyPRO Working Group. She is on the editorial review board of several International journals, including Clinical Cancer Research, Annals of Oncology, The Oncologist and Clinical Breast Cancer.

    Pierfranco Conte is Full Professor of Oncology at the University of Padova, Italy, Director of the Division of Medical Oncology 2 at the Istituto Oncologico Veneto in Padova and Chairman of Rete Oncologica Veneta. He specialized in Clinical Oncology, Clinical Immunology and Haematology. Throughout his career, Prof Conte has been involved in the development of new regimens for the treatment of solid tumors, with special emphasis on breast and ovarian cancer. He was Principal Investigator of numerous research projects supported by the National Research Council (CNR), the Italian Association for Cancer Research (AIRC), the Ministry of Health and the Ministry of Education and Research. He has published more than 300 papers in peer-reviewed journals. The majority of these discuss the biological characterization of breast and ovarian cancer and clinical trials in these disorders. Prof Conte is the recipient of the 2007 “Claude Jacquillat” Award for Achievement in Clinical Oncology, the 2015 “Stelle della Fenice in the world” Award and the 2018 “AIOM: Promotion of clinical research in Italy” Award.

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