Immunotherapy in small cell lung cancer: one step at a time: a narrative review.
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ABSTRACT:
SUBMITTER: Dumoulin DW
PROVIDER: S-EPMC8264327 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Immune checkpoint inhibitors (ICIs) have significantly improved overall survival (OS) in metastatic non-small cell lung cancer (m-NSCLC). However, not all patients with m-NSCLC benefit from ICIs, and resistance to ICIs is an emerging challenge. The tumour microenvironment (TME) is immunosuppressive, and provides a myriad of mechanisms to facilitate escape of cancer cells from immune surveillance. The TME may also dampen the response to ICIs by inhibiting T cell effector responses. The poor prognosis of m-NSCLC has led to investigation of ICIs combined with other treatments with the intention of modulating the TME and sensitizing tumours to the effects of ICIs. Stereotactic ablative radiotherapy (SABR) in combination with ICIs is an area of intense interest. SABR is thought to evoke a pro-immunogenic response in the TME, with the capacity to turn a "cold", unresponsive tumour to "hot" and receptive to ICI. In addition to improved local response, SABR is postulated to produce a heightened systemic immune response when compared to conventional radiotherapy (RT). Preclinical studies have demonstrated a synergistic effect of SABR + ICIs, and clinical studies in m-NSCLC showed safety and promising efficacy compared to systemic therapies alone. To optimize ICI + SABR, ICI choice, combinations, dosing and length of treatment, as well as sequencing of ICI + SABR all require further investigation. Appropriate sequencing may depend on the ICI(s) being utilized, with differing sites of metastases possibly eliciting differing immune responses. Single versus multisite radiation is controversial, whilst effects of irradiated tumour volume and nodal irradiation are increasingly recognized. Taken together, there is strong preclinical and biological rationale, with emerging clinical evidence, supporting the strategy of combining SABR + ICIs in m-NSCLC.
| S-EPMC8264312 | biostudies-literature
Project description:Small-cell lung cancer (SCLC) represents 10-15% of all lung cancers and has a poor prognosis. Thoracic radiotherapy plays a central role in current SCLC management. Concurrent chemoradiotherapy (CTRT) is the standard of care for localised disease (stage I-III, limited-stage, LS). Definitive thoracic radiotherapy may be offered in metastatic patients (stage IV, extensive stage, ES-SCLC) after chemotherapy. For LS-SCLC, the gold standard is early accelerated hyperfractionated twice-daily CTRT (4 cycles of cisplatin etoposide, starting with the first or second chemotherapy cycle). Modern radiation techniques should be used with involved-field radiotherapy based on baseline CT and PET/CT scans. In ES-SCLC, thoracic radiotherapy should be discussed in cases of initial bulky mediastinal disease/residual thoracic disease not progressing after induction chemotherapy. This strategy was however not assessed in recent trials establishing chemo-immunotherapy as the standard first line treatment in ES-SCLC. Future developments include technical radiotherapy advances and the incorporation of new drugs. Thoracic irradiation is delivered more precisely given technical developments (IMRT, image-guided radiotherapy, stereotactic radiotherapy), reducing the risks of severe adverse events. Stereotactic ablative radiotherapy may be discussed in rare early stage (T1 to 2, N0) inoperable patients. A number of current clinical trials are investigating immunoradiotherapy. In this review, we highlight the current role of thoracic radiotherapy and describe ongoing research in the integration of biological surrogate markers, advanced radiotherapy technologies and novel drugs in SCLC patients.
| S-EPMC8107758 | biostudies-literature
Project description:Immunotherapy has radically changed the clinical management of patients with cancer in recent years. Immune checkpoint inhibitors (ICIs) reversing the immunosuppressive effects of the tumor microenvironment are one type of immunotherapy, several of which are approved by the US Food and Drug Administration (FDA) as first-line treatments for patients with non-small cell lung cancer (NSCLC). However, response rates to ICIs are around 19-47% among patients with advanced NSCLC. As a result, the development of combined ICI and radiotherapy has begun with the aim of strengthening patients' antitumor immunity. Radiotherapy with substantial technological improvements not only achieves local tumor control through the induction of deoxyribonucleic acid (DNA) damage in irradiated regions, but also has the potential to mediate immunostimulatory effects that could result in tumor regression beyond irradiated regions. At present, numerous preclinical and clinical research are investigating the efficiency and safety of combining ICI with radiotherapy. The PACIFIC trial showed that combining chemoradiotherapy with ICI could improve clinical outcomes. In this review, we summarize the rationale for combining radiotherapy with immunotherapy. We also discuss the opportunities and challenges of combination therapy, including the timing of radiotherapy, optimal dose and fractionations, radiotherapy target and target volume, acquired resistance, patient selection, and radioimmunotherapy toxicity.
| S-EPMC7653139 | biostudies-literature
Project description:Despite declining smoking rates, lung cancer remains the second most common malignancy in the United States and the leading cause of cancer-related mortality. Non-small cell lung cancer (NSCLC) comprises roughly 85% of cases, and patients tend to present with advanced disease. Historically, concurrent chemoradiotherapy (CRT) has been the standard of care for stage III unresectable NSCLC but outcomes even with multimodal therapy have remained relatively poor. Efforts to improve outcomes through radiation dose escalation with conventional dose fractionation were unsuccessful with RTOG 0617, demonstrating significantly decreased overall survival (OS) with high dose radiation with respect to standard therapy. The recent PACIFIC trial established a new role for consolidative immune checkpoint blockade therapy after CRT using the programmed death ligand 1 (PD-L1) inhibitor durvalumab, by demonstrating significantly improved progression free survival and OS. Although promising, the addition of immunotherapy to multimodal therapy has generated debate regarding the most effective immune pathways to target, appropriate sequencing of therapy, most effective radiation techniques, and toxicity-related concerns. This review will highlight recent and ongoing trials in unresectable, locally advanced NSCLC that incorporate chemotherapy, radiation, and immunotherapy with an emphasis on analysis of treatment-related toxicities and implications for future study design.
| S-EPMC7653152 | biostudies-literature
Project description:Preclinical and early clinical evidence suggest that radical radiotherapy of oligometastatic disease in non-small cell lung cancer (NSCLC) patients can impact outcomes with relatively limited toxicity. Whilst data from phase 2 randomized trials suggesting an improved overall survival (OS) with this treatment is promising, it has also illustrated the heterogeneity in this patient population and treatment. Oligometastatic disease in itself comprises a broad spectrum of patients, in terms of tumor load and location, stage of the disease and treatment history. This real-life variety in patient characteristics is often reflected in studies to a certain extent, hinting to the fact that all might benefit from radical radiotherapy to limited metastatic disease, yet leaving the question unanswered as to whom the ideal candidate is. Furthermore, differences between and within studies with regards to treatment modality, timing, radiation technique, and radiation dose are substantial. Also, preclinical and early clinical trials suggest that radiotherapy can work synergistically with checkpoint inhibitors by acting as an in situ cancer vaccine, therefore the combination of these two treatments in oligometastatic patients might entail the largest benefit. Ongoing randomized controlled phase 3 trials and prospective registry trials will further elucidate the true extent of benefit of this local treatment strategy and aid in identifying the ideal patient population and therapy. The current narrative review summarizes the clinical evidence on radiotherapy for oligometastatic NSCLC and highlights the remaining unknowns.
| S-EPMC8350107 | biostudies-literature
Project description:Patients with oligometastatic disease (OMD) non-small cell lung cancer (NSCLC) are considered as a subgroup of metastatic NSCLC that can obtain long-term survival or even cure. Oligometastatic refers to a state of a limited number of metastases in a limited number of organs. In clinical guidelines it is stated that patients with oligometastatic NSCLC can benefit from the addition of local radical therapy (LRT) to systemic therapy. With the introduction of minimally invasive surgery, advances in interventional radiology and stereotactic radiotherapy (SRT), LRT is becoming feasible for more and more patients. Furthermore, the introduction of immune checkpoint inhibitors (ICI) in the treatment landscape of advanced NSCLC has improved the survival of these patients. Importantly, the use of ICI in combination with LRT is also of interest in the subgroup of NSCLC patients with OMD. For example, it has been suggested that SRT may synergize with ICI as several preclinical studies reported an increased tumor antigen release, improved antigen presentation, and T-cell infiltration in irradiated tumors. In this narrative review, we describe the current evidence of immunotherapy treatment in OMD NSCLC, with a focus on future trial design and problems that need to be addressed.
| S-EPMC8350101 | biostudies-literature
Project description:ObjectiveThe objectives of this review are to discuss: the definition, clinical and biologic features of oligometastatic non-small cell lung cancer (NSCLC), as well as the concept of treating oligoprogression in oligometastatic NSCLC.BackgroundA substantial proportion of patients diagnosed with lung cancer present with metastatic disease, and a large portion of patients who present with localized disease later develop metastases. Oligometastatic NSCLC is defined as an intermediate state between localized and widespread metastatic disease, where there may be a role for curative localized therapy approach by treating the primary tumor and all metastases with radiotherapy or surgery. Despite the increasing application of this approach in patients with lung cancer, the identification of patients who might benefit from this approach is yet to be well characterized.MethodsAfter a systematic review of the literature, a PubMed search was performed using the English language and the key terms: oligometastatic, non-small cell lung cancer (NSCLC), localized consolidative treatment (LCT), biomarkers, biologic features, clinical features. Over 500 articles were retrieved between 1889-2021. A total of 178 papers discussing the definition, clinical and biologic factors leading to oligometastatic NSCLC were reviewed and included in the discussion of this paper.ConclusionsOligometastatic NSCLC is a unique entity. Identifying patients who have oligometastatic NSCLC accurately using a combination of clinical and biologic features and treating them with localized consolidative approach appropriately results in improvement of outcome. Further understanding of the molecular mechanisms driving the formation of oligometastatic NSCLC is an important area of focus for future studies.
| S-EPMC8350108 | biostudies-literature
Project description:Small-cell lung cancer (SCLC) is an aggressive tumor type with limited therapeutic options and poor prognosis. Chemotherapy regimens containing platinum represent the cornerstone of treatment for patients with extensive disease, but there has been no real progress for 30 years. The evidence that SCLC is characterized by a high mutational burden led to the development of immune-checkpoint inhibitors as single agents or in combination with chemotherapy. Randomized phase III trials demonstrated that the combination of atezolizumab (IMpower-133) or durvalumab (CASPIAN) with platinum-etoposide chemotherapy improved overall survival of patients with extensive disease. Instead, the KEYNOTE-604 study demonstrated that the addition of pembrolizumab to chemotherapy failed to significantly improve overall survival, but it prolonged progression-free survival. The safety profile of these combinations was similar with the known safety profiles of all single agents and no new adverse events were observed. Nivolumab and pembrolizumab single agents showed anti-tumor activity and acceptable safety profile in Checkmate 032 and KEYNOTE 028/158 trials, respectively, in patients with SCLC after platinum-based therapy and at least one prior line of therapy. Future challenges are the identification predictive biomarkers of response to immunotherapy in SCLC and the definition of the role of immunotherapy in patients with limited stage SCLC, in combination with radiotherapy or with other biological agents.
| S-EPMC7565004 | biostudies-literature
Project description:The leading cause of cancer-related deaths in the United States continues to be lung cancer. Approximately 25-30% of patients are diagnosed with locally advanced non-small cell lung cancer (NSCLC). Concurrent chemoradiation with a platinum-based doublet is the current standard of care for patients with inoperable stage III NSCLC. Unfortunately, only 15-20% of patients treated with definitive chemoradiation are alive at 5 years. Thus, there has been a major unmet need in this area. In this article, we summarize the current status and ongoing clinical trials incorporating immunotherapy into the management of inoperable stage III NSCLC, and we also present our perspective on the future directions.
| S-EPMC6586171 | biostudies-literature
Project description:Currently, immunotherapy is widely used in the treatment of various stages of non-small cell lung cancer. According to clinical experience and results of previous studies, immunotherapy as neoadjuvant therapy seems to exhibit better efficacy against early resectable non-small cell lung cancer as compared to advanced lung cancer, which is often defined as unresectable non-small cell lung cancer. However, this observation has not been established in clinical studies. This systematic review aimed to evaluate the efficacy of immunotherapy in early and late lung cancer, wherein objective response rate (ORR) and disease control rate (DCR) were used as evaluation indexes. The present study also evaluated the safety of immunotherapy in early and late lung cancer, wherein the rate of treatment-related adverse reactions (TRAEs) was used as an indicator. Electronica databases, including PubMed, Cochrane Library, Embase, and other databases, were searched to identify relevant studies. Besides this, all the available reviews, abstracts, and meeting reports from the main international lung cancer meetings were searched manually. ORR, DCR, and TRAEs were extracted as the primary outcomes. A total of 52 randomized controlled trials involving 13,660 patients were shortlisted. It was observed that immunotherapy alone significantly improved DCR in early lung cancer in comparison to advanced lung cancer. Importantly, the improvement in ORR was not to the same extent as reported in the case of advanced lung cancer. The combination of immunotherapy with other therapies, especially immunochemotherapy, significantly improved ORR and DCR in early lung cancer. In terms of safety, immunotherapy either alone or in combination with other therapies exhibited a better safety profile in early lung cancer than in advanced lung cancer. Altogether, the benefits of immunotherapy in early lung cancer appeared to be better than those observed in advanced lung cancer, especially with the regard to the regimen of immunotherapy in combination with chemotherapy. In terms of safety, both immunotherapy alone and its combination with chemotherapy were found to be safer in early lung cancer as compared to advanced lung cancer.
| S-EPMC9641944 | biostudies-literature