Small cell lung cancer trial

Methods: We did this phase 3 randomised controlled trial at 42 hospitals: 16 in Netherlands, 22 in the UK, three in Norway, and one in Belgium. They were randomly assigned to receive either thoracic radiotherapy 30 Gy in ten fractions or no thoracic radiotherapy.

All underwent prophylactic cranial irradiation. The primary endpoint was overall survival at 1 year in the intention-to-treat population. Patients who received chemotherapy either received carboplatin or etoposide.

About patients with untreated extensive-stage small-cell lung cancer participated in the double-blind study. Participants were required to have adequate major organ function for eligibility. The study subjects received the serplulimab via injection.

The small-cell lung cancer clinical trial took place in Shanghai, China in collaboration with Henlius Biotech. Current clinical studies involving serplulimab investigate its potential success in treating other cancers.

Serplulimab may serve as a possible treatment option for gastric, colorectal, cervical, liver, and squamous cell cancers. The interplay between adhesion, migration, survival and proliferation may be relevant to the strong metastatic potential of SCLC cells.

SCLC cells have the capacity to communicate with their microenvironment in an autocrine, paracrine and endocrine manner. Several studies suggest that neuropeptides produced by SCLC cells promote tumour cell survival and proliferation by autocrine and paracrine loops 93 — The presence of endocrine paraneoplastic syndromes in patients with SCLC , imply that long-range communication exists between SCLC cells and other cells in the body but it is unclear if these systemic effects have a role in SCLC growth.

Overall, the extent of the molecules secreted by SCLC cells, the cell types reached by these molecules, and the effects of these interactions on tumour growth and response to treatment remain largely unknown. The exceptionally rapid proliferative rate of SCLC cells suggests that they might be selectively dependent on the biosynthetic pathways required for cell replication.

Additional potential metabolic vulnerabilities in SCLC have begun to be explored, including glycolytic and lipid synthesis pathways — Nevertheless, the metabolism of SCLC cells is only beginning to be investigated. Patients with SCLC have exceptionally high numbers of CTCs, providing a unique opportunity to investigate possible drivers of metastatic seeding, including genomic alterations, expression changes and heterogeneity 2 , 32 , 53 , — Small clusters of malignant cells have been observed in both blood and lymphatic vessels in patients with SCLC: adhesion between CTCs in these small clusters may be an important aspect of cell survival during metastasis 2.

SCLC tumours growing in the lungs of genetically engineered mice often metastasize to the pleural space, lymph nodes and distant organs, including the liver, similar to what is observed in patients One notable exception is the lack of brain metastasis in SCLC mouse models, which might reflect either biological differences between human and mouse tumours or the relatively rapid death of mice from their primary tumours and liver metastases.

The analysis of primary tumours and metastases in mouse models identified the transcription factor NFIB as a major determinant of SCLC metastasis — One mechanism underlying the pro-metastatic role of NFIB in SCLC is by the induction of gene expression programmes related to cell adhesion, cell migration and neuronal differentiation 90 , Mechanisms other than NFIB remain poorly understood but factors associated with neuronal differentiation and migration are also implicated in SCLC metastatic potential 83 , SCLC cells have a high tumour mutation burden and, on this basis, are predicted to induce strong T cell responses.

Indeed, some patients with SCLC with paraneoplastic neurological syndromes exhibit high immune activity and tend to have a better prognosis than patients without these syndromes The presence of immune cells with suppressive properties, such as regulatory T cells, in the SCLC tumour microenvironment may further promote immune evasion , Other mechanisms include the suppression of antigen-presenting cells by neuropeptides secreted by SCLC cells It remains unknown whether the interactions between immune cells and SCLC cells are similar in human tumours and genetically engineered mouse models.

Of note, mouse tumours have a low tumour mutation burden whereas human SCLC is among the most highly mutated cancers 24 , 37 , which could substantially affect T cell responses. The activation of macrophages and the development of chimeric antigen receptor-expressing T cells specifically targeting SCLC might help to bypass some of the current lack of efficacy of T cells against SCLC.

While the SCLC tumour mutational landscape does not seem to define subtypes, the expression of specific transcription factors provides a first framework to differentiate biologically distinct SCLC subtypes. Differences between the transcription programmes of these four subtypes include distinct degrees of neuroendocrine differentiation and differences in metabolism. This emerging molecular classification also serves as a framework within which to further refine additional subtypes FIG.

Importantly, single-cell analyses are likely to help define how intratumoural heterogeneity is connected to these and possibly new subtypes , Analogous to the transition of lung adenocarcinoma to SCLC, an important aspect of future studies will be to monitor how SCLC tumours of certain subtypes evolve with time and treatment. Of note, mouse models generated to date only model the SCLC-A and SCLC-N subtypes , and the development of new models combining various genetic alterations and different putative cell-of-origin types 56 will be key to modelling all subtypes, possibly helping to define new subtypes and to investigate intratumoural and intertumoural heterogeneity in SCLC.

A few other genetic and epigenetic alterations have been associated with specific subtypes, including the differential expression of MYC family members and mutations in NOTCH family genes, but most recurrent mutations are found in all subtypes.

Selected genes of interest, with chromosomal locations and frequency in SCLC tumours percentage in parentheses are indicated. This personalized approach would of course require the development of a number of new therapeutic approaches and these approaches are likely to have to be combined to combat the plasticity of SCLC cells and the heterogeneity of SCLC tumours.

A key aspect of such therapeutic approaches will also be to block the transitions between different states, which might be achieved through the targeting of epigenetic regulators. SCLC is a high-grade malignant epithelial tumour. A confirmed diagnosis relies on characteristic light microscopic features of the tumour with haematoxylin and eosin staining histopathological features are described below. Immunohistochemistry can be used to exclude other diagnoses.

Combined SCLC has an additional component of non-small-cell carcinoma, which can be of any non-small-cell histological subtype.

Cytology is a powerful tool that is sometimes more definitive than histology of small biopsies, which in SCLC often have crush artefacts. Distinct clinical characteristics of SCLC include the predominantly central location of the primary tumour in the major airways and the often extensive extrapulmonary metastatic spread at presentation. Owing to the rapid tumour growth and widespread metastases, most patients with SCLC are symptomatic at presentation and the duration of symptoms is typically less than 3 months.

Bulky mediastinal involvement is common. Intrathoracic local growth explains frequent symptoms at presentation, including cough, wheeze, dyspnoea, haemoptysis, superior vena cava compression resulting in upper body oedema and flushing, oesophageal compression with dysphagia, and recurrent laryngeal nerve compression with left vocal cord paralysis.

Fatigue, anorexia, weight loss and neurological complaints are associated with distant spread. The brain, liver, adrenal glands, bone and bone marrow are common sites of metastasis. SCLC is frequently associated with paraneoplastic syndromes , Common SCLC paraneoplastic endocrinopathies include syndrome of inappropriate anti-diuretic hormone and Cushing syndrome; paraneoplastic neurologic syndromes caused by autoantibodies include Lambert—Eaton syndrome, encephalomyelitis and sensory neuropathy syndromes.

Rare manifestations include dermatomyositis, hyperglycaemia, hypoglycaemia, hypercalcaemia and gynecomastia breast tissue swelling in males. These antibody-dependent syndromes reflect common aberrant activation of humoral B-cell mediated immunity in SCLC; interestingly, immune checkpoint blockade, which activates cellular T cell-mediated immune responses, showed no apparent increase in paraneoplastic phenomena in patients with SCLC — Given the aggressive nature of SCLC, diagnostic and staging work-up should be performed as quickly as possible after presentation.

Owing to the usual central location of the tumour, biopsies are often obtained by bronchoscopy with or without endobronchial ultrasonography; alternatives include mediastinoscopy, transthoracic biopsies or thoracoscopy. Depending on accessibility, a preferred option can be the biopsy of a distal metastatic site. The diagnosis is only confirmed by histopathological examination aided by cytology A higher CTC count is a negative prognostic factor for patients with SCLC 2 , but is rarely used in practice outside of the clinical trial setting.

The radiological findings in SCLC are similar to those of other lung cancers, with a tendency for tumours to be larger, centrally located and at a more advanced stage at presentation , Bulky mediastinal lymph nodes are common. Metastatic spread is often radiologically evident and may include pleural and pericardial effusions.

The tumour—node—metastasis TNM classification is preferred to the previous staging system of the Veterans Administration Lung Study Group VALSG , which separates limited-stage disease tumour confined to one hemi-thorax and one radiation port; no malignant pleural or pericardial effusion from extensive-stage disease disease not meeting criteria for limited stage TNM staging provides better anatomic discrimination for the measurement of outcome, prognostic information and more precise lymph nodal staging , , The use of the TNM classification is therefore beneficial in defining optimal treatment strategies in clinical trials.

Access to optimally accurate staging modalities represents a clear limitation in low-income countries. Clinicians and cancer registrars are strongly encouraged to use the TNM eighth edition staging system Nonetheless, the VALSG staging system is still widely used in both designing clinical trials and presenting data from them, as it effectively distinguishes patients treated primarily with CRT limited-stage disease from those treated with systemic chemotherapy or chemo-immunotherapy extensive-stage disease.

Cardinal histopathological diagnostic criteria include small tumour cells with a round to fusiform shape, scant cytoplasm, finely granular nuclear chromatin, and absent or inconspicuous nucleoli. Apoptotic figures are numerous and necrosis is usually extensive.

Nuclear moulding is frequent since cells are situated in close proximity. This example demonstrates a predominant area with classic SCLC features, including the expression of CD56 and INSM1, along with a discrete subdomain with contrasting squamous SQ cell carcinoma features, including a more abundant cytoplasm and the expression of cytokeratin 5 CK5 , CK6 and p Densely packed tumour cells typically appear sheet-like with an absence of architectural features.

They occasionally show rosettes rose-shaped collections of cells and, less commonly, nests rounded groups of cells separated by stroma , trabeculae ribbons and peripheral palisading parallel arrangement of nuclei at the periphery of nests. Neuroendocrine features may be more evident on surgical specimens than on bronchial biopsy samples Crush artefacts are frequent. Combined SCLC is more frequently recognized in surgical samples than in small biopsy samples, possibly due to increased crush artefact and fewer cells in the latter , The clinical presentation, response to chemotherapy and survival rates of patients with combined SCLC are similar to those of patients with pure SCLC, although the frequency of peripheral and resectable tumours is higher for combined SCLC In theory, the diagnosis of SCLC relies on light microscopy-based histopathological analysis although, in current practice, immuno histochemistry is commonly performed to differentiate SCLC from other diagnoses.

Cytological preparations can have diagnostic utility, especially when biopsies are small, crushed or necrotic Cytological smears often show isolated tumour cells or loose aggregates with nuclear moulding owing to reciprocal deformation of compressed nuclei. Nucleoli are absent or inconspicuous and the cytoplasm is minimal, resulting in a high nucleus to cytoplasm ratio.

Primary differential diagnoses in SCLC cases include other neuroendocrine lung tumours, NSCLC and, in particular, basaloid carcinoma, extrapulmonary small-cell tumours and lymphoma.

The cytoplasm is more prominent in carcinoid tumour cells than in SCLC tumour cells and necrosis is often extensive in SCLC tumours and absent or focal in carcinoid tumours. Compared with SCLC, LCNEC tumour cells have a more abundant cytoplasm, a polygonal shape with a distinct cell border, vesicular nuclear chromatin and often visible nucleoli Basaloid carcinoma, a subtype of squamous cell carcinoma, shares the small cell size with SCLC and can be mistaken for SCLC in small or crushed biopsies Ewing sarcoma with EWSR1 rearrangement and other small round-cell sarcomas with rearrangements other than EWSR1 may be considered; compared with SCLC, cells in these tumours are more dyscohesive, the mitotic rate is lower, cytokeratin expression is negative or very focal, and they stain for CD99 also known as MIC2 — Appropriate fluorescence in situ hybridization FISH techniques should be applied in case of doubt.

Screening by low-dose CT in patients at risk for lung cancer smokers and ex-smokers has detected newly diagnosed SCLC cases. The National Lung Screening Trial NLST involved random assignment of over 53, individuals at risk for lung cancer based on age and smoking history to annual screening for 3 years with either annual low-dose CT or chest X-ray and detected SCLC tumours in individuals The NELSON screening trial involved over 15, individuals at risk of lung cancer and confirmed an overall reduction in lung cancer mortality with annual low-dose CT screening, but data analyses specific to SCLC have not been reported Although multiple protein biomarkers of SCLC can be detected in patient serum , these have not been translated into an early intervention strategy.

To date, there is no approach to early detection that has been shown to be effective for SCLC. In non-metastatic SCLC, the goals of treatment include achieving durable control of thoracic disease and reducing the risk of metastatic dissemination.

Local treatment options to control thoracic disease include surgery and radiotherapy. Chemotherapy can both augment the local efficacy of radiation and potentially treat micrometastatic disease. The standard chemotherapy regimen in this setting is cisplatin—etoposide, which has not changed for the past three decades.

The advantages of this regimen include that it can be delivered at full dose in patients treated with concurrent CRT and has a well-established toxicity profile. In patients who are not suitable for cisplatin, carboplatin—etoposide can be considered Other chemotherapeutic drugs, such as irinotecan or paclitaxel, have activity in these patients but have not shown superiority Improved outcomes with immunotherapy in early-stage NSCLC and in metastatic SCLC , have led to the investigation of immune checkpoint inhibitors as concurrent primary or adjuvant therapies but these are still considered experimental.

Drugs that received full and accelerated FDA approvals are included. Rare cases of small-cell lung cancer SCLC presenting as isolated pulmonary nodules tumour—node—metastasis TNM stage I may be amenable to surgical resection or treatment with stereotactic ablative radiotherapy SABR and adjuvant chemotherapy. For recurrent disease, current approved agents for second-line treatment in the USA include topotecan and lurbinectedin; for third-line and beyond, the indicated anti-PD1 immunotherapy drugs can be considered but their role is also unclear in patients treated with first-line chemoIO.

Prophylactic cranial irradiation PCI is also part of the standard management in most patients with non-metastatic SCLC who respond to initial treatment, as it significantly reduces the risk of brain metastases and improves survival 3 , The management of these patients is controversial owing to a lack of randomized controlled trials comparing surgical to non-surgical approaches in the era of modern staging and treatments. At least three local treatment options are available for these patients: surgery, fractionated radiotherapy dividing the total dose of radiation into multiple smaller doses and stereotactic radiotherapy.

Only two phase III trials, one performed in the s and the other in the s , , have been reported. In , a systematic review stated that, although currently available randomized controlled trial data do not support a role for surgical resection in the management of SCLC, this conclusion is of limited value owing to a lack of contemporary data and the low quality of available evidence This uncertainty has led to inconsistencies in national and international treatment guidelines with regards to the role of surgery in managing SCLC Consequently, deciding between surgical and non-surgical approaches is challenging for both clinicians and patients.

Primary surgical resection is generally limited to the treatment of patients with clinical stage I or II cT1—T2N0 disease , The aim of surgical treatment is to achieve a microscopically margin-negative resection R0 resection After surgical resection, adjuvant chemotherapy should be given and there is no role for adjuvant thoracic radiotherapy unless an incomplete resection R1—R2 was performed or pathology reveals unforeseen mediastinal nodal involvement N2 The evidence available on fractionated radiotherapy in early-stage SCLC is limited, as the TNM classification was not integrated for the staging of patients in historical clinical trials of CRT.

Promising data from small retrospective studies on the role of stereotactic ablative radiotherapy for early-stage SCLC have led to its inclusion as an option in guidelines for the treatment of patients with peripheral T1—T2N0M0 disease , The role of PCI in early-stage SCLC is controversial, particularly in stage I, owing to its lower risk of development of brain metastases compared to locally advanced disease — Surgery is generally not a treatment option in these patients.

The role of radiotherapy with concomitant chemotherapy is well established in the management of locally advanced SCLC The standard of care for patients with a performance status of 0—1 meaning at least ambulatory and able to carry out work of a light or sedentary nature is twice-daily thoracic radiotherapy 45 Gy in 3 weeks with concurrent cisplatin—etoposide , If twice-daily radiotherapy cannot be delivered for patient-specific or practical reasons, once-daily radiotherapy is a reasonable alternative Evidence from randomized controlled trials and meta-analyses favours the initiation of radiotherapy as early as is feasible in the course of CRT, preferably with the first or second cycle of chemotherapy , , — In cases of bulky disease at presentation, the dose to the organs at risk may not permit the early administration of thoracic radiotherapy.

In such cases, radiotherapy can be postponed until the start of the third cycle of chemotherapy, at which time it is likely that a reduction in disease volume has been achieved In the sequential setting, the typical radiotherapy approach is to treat the post-chemotherapy primary tumour volume and the pre-chemotherapy nodal volume PCI significantly decreases the risk of symptomatic brain metastases and increases overall survival in patients with non-metastatic SCLC , In such patients, a shared decision process should be encouraged For over three decades, the first-line chemotherapy for newly diagnosed metastatic SCLC has consisted of a platinum agent cisplatin or carboplatin together with etoposide 1.

A phase III clinical trial reported superiority of cisplatin—irinotecan over cisplatin—etoposide in a Japanese population , but two subsequent randomized studies in the USA failed to confirm this result , Multiple randomized phase III studies have demonstrated the statistically significant benefits of adding an immune checkpoint inhibitor to first-line chemotherapy in patients with newly diagnosed metastatic SCLC — The addition of either of two anti-PDL1 monoclonal antibodies atezolizumab or durvalumab to a standard platinum—etoposide backbone, with continuation of immunotherapy as maintenance, improved both progression-free survival and overall survival , The addition of the anti-PD1 antibody pembrolizumab in the same context resulted in a similar benefit but was only statistically significant for progression-free survival These observations imply that there is a subset of patients with SCLC who derive durable benefit from immunotherapy, although the majority do not.

The role of tumour mutation burden as a predictive biomarker of SCLC response to immunotherapy is controversial, as the Checkmate analysis suggests a correlation but the IMPOWER blood-based analysis showed no evident association , Defining tumour and host characteristics associated with immunotherapy response is an area of active investigation.

Until , the only standard of care second-line therapy for recurrent meta static SCLC was the topoisomerase I inhibitor topotecan. The anti-PD1 monoclonal antibodies nivolumab and pembrolizumab were granted accelerated approval for third-line use , , although the role of these agents is unclear in patients whose disease has progressed on first-line immune checkpoint inhibitors. Although not approved for the specific indication by regulatory authorities, many other cytotoxic agents have clinical activity in SCLC and are included as options in treatment guidelines for recurrent SCLC, including the nivolumab—ipilimumab combination, paclitaxel, docetaxel, irinotecan, temozolomide and oral etoposide 3.

Retreatment with a platinum doublet in patients with response maintained for at least 3 months after first-line treatment is another reasonable choice. Radiotherapy has traditionally been reserved for the palliation of symptoms in patients with advanced disease, including in those who have poor responses to chemotherapy. Clinical trials to resolve this controversy are ongoing Treatment for leptomeningeal metastases remains a major unmet need.

A European trial that randomly assigned patients to consolidative thoracic radiotherapy or best supportive care found no statistical difference in the primary endpoint of 1-year survival yet a post hoc analysis suggested improvement in 2-year survival with radiotherapy, with a low rate of toxicity The benefit of this treatment was more pronounced in patients with residual intrathoracic disease. An important unanswered question in the metastatic setting is the integration of thoracic radiotherapy, PCI and immunotherapy.

Periodic CT scanning is recommended to identify recurrence as early as possible and to offer salvage treatment if appropriate. However, there is a paucity of data supporting the frequency of imaging and its effect on survival. A further rationale for regular imaging of patients with SCLC is the high risk of developing second malignancies, which are generally tobacco induced, in the lungs and other organs , The follow-up of patients with SCLC, particularly those with non-metastatic disease, should also include the management of the multiple comorbidities often associated with this disease including cardiac and respiratory comorbidities generally caused by smoking 19 , Patients may also have treatment-related adverse effects, such as pulmonary fibrosis or cardiac complications, which may benefit from specialist input The management of these patients by a multidisciplinary team that includes non-oncology specialists is likely to provide better symptom control, improved quality of life and, possibly, improved outcomes.

At the time of diagnosis and during follow up, patients should be actively encouraged to stop smoking. Indeed, continuing smoking after a diagnosis of SCLC is associated with a risk of developing second primary tumours as well as with a risk of cardiovascular, respiratory and cerebrovascular disease, leading to poorer suvival , Personalized treatment is at the heart of modern oncology and should consider the risk to benefit ratio of therapy for each individual patient.

Considering the poor outcome in the majority of patients with SCLC, open and honest discussions that include prognosis, goals of care and supportive care should take place early on in the management of patients. To the greatest extent possible, all patients should be discussed and managed by a multidisciplinary team, including specialist nurses and supportive-care specialists. When treatment is discussed, patients should be clearly informed about the short-term and long-term adverse effects of treatment and their effect on quality of life.

This information is particularly important for patients with metastatic disease who have limited life expectancy and in whom the risk of toxicity should not outweigh the symptomatic benefit of treatment. As SCLC is at diagnosis an exceptionally chemoresponsive disease, patients with poor performance status attributable to disease may substantially improve with the initiation of chemotherapy.

In patients with non-metastatic SCLC, improvements in survival rate over the past 20 years have led to an increasing focus on limiting the long-term toxicity of curative-intent treatment, such as CRT and PCI.

The use of modern radiotherapy techniques with strict dose limits for in-field organs have led to a reduction in adverse events related to thoracic radiotherapy and chemotherapy toxicity, such as radiation oesophagitis and pneumonitis However, data on longer-term toxicities are limited, including the effect of lung fibrosis on respiratory function and quality of life.

The rare patients with metastatic SCLC who respond exceptionally well to immunotherapy have further raised the importance of recognizing and minimizing the effect of treatment-related toxicities box 1. Her disease recurred and progressed in the chest, abdomen and pelvis after treatment with cisplatin, etoposide and concomitant radiation, prophylactic cranial irradiation PCI , carboplatin and irinotecan, palliative radiation to the pelvis, and temozolomide.

She started participation in an anti-PD1 immunotherapy trial in and continued on this study for more than 3 years. She has been off all therapy for the past 2 years, with no evident disease. While highly exceptional, her experience serves as a proof of principle that this disease can respond durably to immunotherapy.

Thus, I became quite familiar with what NSCLC-ers had to endure, often including some form of lung surgery that curtailed their activity due to difficulty breathing.

Since surgery is not typically an option for SCLC, I never had any, and was able to breathe just fine. Compared to the others, this was a huge plus in my book. It was a very intense time, like being forced at gunpoint to drive through a tunnel that had an unknown destination. For a normally cheery person like me, I felt uncharacteristically compelled to review the worthiness of my life and figure out what my burial plans could be.

Knowing I had those factors might have given me hope earlier in my treatment. The improved outcomes, particularly for patients with non-metastatic SCLC, has also prompted increased concern from both clinicians and patients regarding the risk of neurotoxicity associated with PCI Memory loss, intellectual deficit, dementia and ataxia have been reported, often in patients with cerebral atrophy and white matter changes on brain imaging.

It is recognized that, in addition to PCI, a number of factors can affect neurocognition, including underlying comorbidities caused by smoking, paraneoplastic syndromes, underlying anxiety and depression, chemotherapy, and SCLC itself. This is supported by studies demonstrating impairment in neuropsychological tests in patients with SCLC, even before PCI is given , Minimizing neurotoxicity is an important goal of ongoing clinical trials, including those evaluating the benefit of hippocampus-sparing PCI and comparing PCI to MRI surveillance Progress on several fronts is defining new avenues of investigation and providing renewed hope for patients with this recalcitrant cancer.

Many new insights regarding SCLC biology have stemmed from the development and analysis of representative genetically engineered mouse models of SCLC and these insights have been complemented and reinforced by parallel analyses of SCLC cell lines, patient-derived in vivo models and primary human tumours Analyses of mechanisms of in vivo-acquired therapeutic resistance in SCLC through both transcriptomic 77 and proteomic 46 approaches have revealed new potential tumour-specific vulnerabilities.

The new understanding of key transcriptional drivers of SCLC phenotypes, defining subtypes of disease with distinct dependencies, might help to focus therapeutic clinical research on patient populations that are most likely to respond to particular targeted agents Technological improvements in imaging and in the advanced delivery of radiotherapy have increased the survival rates of patients with localized disease, while reducing the short-term and long-term adverse effects The introduction of immunotherapy as part of standard treatment for many patients with metastatic SCLC has finally led to improvements in overall survival for this cohort of patients with a particularly poor prognosis , These and other advances underscore tangible progress in the management of SCLC and have defined a number of novel therapeutically tractable targets for this disease FIG.

Many key targets highlighted are being actively pursued in completed and upcoming clinical trials. Despite these highlights, SCLC remains a largely lethal disease. Several gaps exist in our understanding of the disease, which contribute to the modest effect that current treatments have had on patient survival. Notably, the societal impact of SCLC could be obviated with effective prevention, especially as the aetiologic agent in oncogenesis is exceptionally clear. SCLC is among the diseases most strongly associated with tobacco carcinogen exposure The importance of global and multifaceted public health advocacy and governmental regulatory approaches to reduce the initiation of smoking and increase smoking cessation cannot be overemphasized.

The effective screening for incipient SCLC is a major and entirely unmet need. Highly sensitive, blood-based detection using mutational, proteomic or multiparameter approaches is an area of active investigation. Preclinical studies suggest the detection of neuroendocrine markers through mass spectrometry as one potential approach Most patients with SCLC die of metastatic disease.

As noted, annual CT screening in a high-risk population fails to detect early-stage SCLC — with or without screening, an identical majority of patients have stage IV disease at diagnosis This observation might imply a biological difference between limited-stage SCLCs, which commonly present with a large primary mass and bulky adenopathy, and extensive-stage SCLCs, which often present with widespread metastases at diagnosis.

Studies have uncovered remarkable intertumoural and intratumoural heterogeneity in SCLC. We are only beginning to dissect how this heterogeneity influences the biology of disease. We are only beginning to understand the extent to which subtype assignments are mutable and whether tumour evolution between subtypes reflects lineage plasticity or differential selection among pre-existing subclones Multiple recurrent mutations affecting epigenetic regulatory pathways in SCLC have been defined 24 , 40 , 41 , 77 ; how these epigenetic pathways could either determine or drive the transition between transcriptional states is unknown.

Despite hypothesized subtype-specific vulnerabilities , the extent to which different predominant subtypes in fact influence clinical prognosis, therapeutic responsiveness and patterns of disease progression has not been defined.

Intratumoural hetero geneity, including a mix of interacting neuroendocrine and non-neuroendocrine subpopulations, has been implicated in metastatic potential in mouse models 39 , but has been less extensively characterized in human tumours. Emerging technical advances in single-cell profiling technologies, including single-cell transcriptional profiling, proteomic profiling and spatial multicolour imaging, are ideally suited to begin to study some of these issues.

The advent of chemo-immunotherapy as a new standard of care for the first-line treatment of metastatic disease , is both a remarkable hallmark of progress and a disappointment. The overall improvement in survival in patients with SCLC from the addition of immune checkpoint blockade is modest relative to that seen in many other solid tumours, despite a highly mutated genome in SCLC tumours.

An intensive focus of clinical research is now on the exploration of complementary pathways to immune activation, including the blockade of alternative immune checkpoints, the use of bispecific T cell engagers or natural killer cell activators, and assessing DNA damage response inhibitors or epigenetically targeted agents as strategies to induce immune-responsiveness in SCLC Similar challenges to improving survival also apply to early-stage and locally advanced SCLC.

Building on the successes in treating metastatic disease, multiple trials are in development or in progress to assess the role of PD1—PDL1 checkpoint blockade in patients treated with CRT. It would be of substantial interest to know if sensitive methods for the detection of circulating tumour DNA in blood and, possibly, in cerebrospinal fluid could be used to identify those patients who might benefit from additional treatment, such as PCI or additional systemic therapies, versus those who are likely to be cured by thoracic CRT alone.

I think a big part of this study, having been talked about so much is that for decades, we really had no improvements in outcomes for patients with small cell lung cancer. We would take every new agent that came along, add it to a platinum etoposide regimen,, and really didn't see a benefit. And this was the first positive study for patients with small cell lung cancer with a checkpoint inhibitor in combination with chemotherapy.