- The addition of immunotherapy to the standard platinum-etoposide backbone with subsequent consolidative thoracic radiation therapy might improve the survival outcomes in well selected extensive-stage small cell lung cancer patients.
- Combining consolidative thoracic radiation therapy with immunotherapy results in the synergistic enhancement of treatment efficacy by affecting the tumor microenvironment and strengthening the antitumor immune response.
- Recent studies demonstrate survival benefits, improved intrathoracic disease control and manageable toxicity profiles for patients treated with consolidative thoracic radiation therapy.
- Further prospective clinical trials are needed to elucidate the efficacy of consolidative thoracic radiation therapy in small cell lung cancer and to identify novel predictive biomarkers of response.
Lung cancer is one of the most common malignancies worldwide and the leading cause of cancer-related deaths in the Western world . Although small cell lung cancer (SCLC) only accounts for approximately 13–15% of all lung cancer cases, it represents the deadliest histological subtype with a 5-year survival rate way below 7% (causing nearly 40 000 deaths each year) . SCLC typically occurs in current or former heavy smokers and is characterized by genomic instability, rapid doubling time, high vascularity, and early metastatic spread [1,2]. Although SCLC has long been assumed to originate from the neuroendocrine cells of the lung, other lung epithelial cells such as the tuft cells may also serve as cells of origin [2,3]. Given its high proliferation rate, approximately two-thirds of the patients present with an extensive-stage (ES) disease at the time of diagnosis when surgical resection is not feasible. Despite the poor survival outcomes of ES-SCLC patients (around 8–10 months from diagnosis), until recently, the standard systemic therapy for these patients constituted of platinum-based chemotherapy in combination with etoposide . Following the encouraging results seen in the IMpower133 trial, the Food and Drug Administration (FDA) agency approved the combination of atezolizumab with carboplatin and etoposide as a first-line treatment for ES-SCLC patients. In this study, the addition of atezolizumab to the standard platinum–etoposide backbone improved both the progression-free survival (PFS) and overall survival (OS) of immunotherapy-treated patients (by 0.9 and 2 months, respectively) [1,2]. Furthermore, the efficacy of prophylactic cranial irradiation (PCI) and consolidative thoracic radiation therapy (cTRT) with continuation of front-line systemic chemo-immunotherapy as maintenance is also under investigation for ES disease [5,6▪].
One of the main reasons behind the lack of a significant breakthrough in the systemic therapy of SCLC patients might be that SCLC is still considered a homogenous disease in the clinics. Accordingly, although recent studies [4,7–9] suggest that SCLC tumors comprise multiple biologically distinct molecular subtypes with the following subtype-specific protein Achaete-Scute Homologue 1 (ASCL1; SCLC-A subtype), Neurogenic Differentiation Factor 1 (NEUROD1; SCLC-N subtype), POU Class 2 Homeobox 3 (POU2F3; SCLC-P subtype) and Yes-Associated Protein 1 (YAP1)/Quadruple negative (SCLC-Y/QN subtype), current clinical study protocols are still based on disease stage. In order to enhance the efficacy of administered therapeutic agents, it will likely be fundamental for future clinical trials to determine the tumors’ molecular subtype for each patient prior to enrollment. Yet, further studies are still needed to elucidate the differences concerning the biological aspects and clinical relevance of these emerging SCLC subtypes. It has already been clarified that SCLC-A and SCLC-N subtypes typically show neuroendocrine patterns, whereas the SCLC-P and SCLC-Y/SCLC-QN subtypes have less neuroendocrine phenotypes and, are therefore, classified as non-neuroendocrine subsets [2,4]. As for their prognostic relevance, our group recently showed that non-neuroendocrine subtypes (SCLC-P and SCLC-QN) are typically associated with better survival outcomes (vs. patients with neuroendocrine SCLCs) and that high ASCL1 expression is an independent negative prognosticator in surgically-treated SCLC .
In this review, we present an overview of the most recent developments and clinical trials in ES-SCLC, focusing in particular on the clinical aspects of cTRT (such as therapy combination, patient selection, radiation technique and dose).
Immunotherapy as an emerging treatment option has brought efficient changes in the clinical management of several solid tumors including non-small cell lung cancer (NSCLC) . Given that many of the immune checkpoint inhibitors’ susceptibility features seen in NSCLC are even more pronounced in SCLC, it was initially suspected that immunotherapy might eventually be more efficient in this malignancy [2,4]. SCLC tumors are strongly linked with tobacco exposure and carry a higher median tumor mutation burden (vs. NSCLC specimens; 9.9 mutations/Mb vs. 6.3–9 mutations/Mb, respectively), which are both predictive factors for responsiveness to immunotherapy in NSCLC [11,12]. Still, immunotherapeutic agents could only partially improve the survival of SCLC patients so far. Nevertheless, based on the results of the IMpower133 and CASPIAN phase III randomized controlled trials, considerable changes were made in the first-line treatment of ES-SCLC patients. In brief, the IMpower133 study (n = 403) investigated the efficacy of atezolizumab in combination with carboplatin and etoposide in previously untreated ES-SCLC patients. All therapeutic agents were administered in every three weeks for four cycles. The median OS in the atezolizumab group was 12.3 months compared to the 10.3 months in the placebo group, whereas the gain in median PFS was 0.9 months . In the CASPIAN study (n = 805), the researchers assessed the efficacy of durvalumab in combination with carboplatin/cisplatin and etoposide with or without tremelimumab. Importantly, the median OS was significantly longer in patients treated with durvalumab plus platinum–etoposide (vs. placebo group, median OSs were 12.9 vs. 10.5 months, respectively), yet tremelimumab therapy was not associated with a significant improvement in OS . The efficacy of pembrolizumab, the first FDA-approved Programmed Cell Death Protein 1 (PD-1) inhibitor, was also examined in the KEYNOTE-604 (n = 452) trial, but no significant difference was found in the OS of ES-SCLC patients . Based on the above results, current therapeutic guidelines (National Comprehensive Cancer Network [NCCN], European Society for Medical Oncology [ESMO], American Society of Clinical Oncology [ASCO] and American Society for Radiation Oncology [ASTRO]) support the use of atezolizumab- or durvalumab-based immunotherapy in combination with platinum-based chemotherapy for four cycles, followed by anti-Programmed Cell Death Ligand 1 (anti-PD-L1) maintenance therapy in ES-SCLC patients with performance status (PS) of 0 or 1 [15–17].
PROPHYLACTIC CRANIAL IRRADIATION
Based on the initial results, PCI improves the survival outcomes of patients with ES-SCLC [18,19]. According to the contemporary ESMO guidelines, PCI is recommended after the first-line treatment only in SCLC patients under the age of 75 with a PS of 0–2, when no sign of progression occurs . Nevertheless, the results of randomized clinical trials concerning the efficacy and general benefit of PCI are still controversial. This is mainly because several main factors are inconsistent in these studies thus hindering their comparability with each other. These factors include among others: examination of the severity of adverse effects, presence or absence of any baseline imaging examination; radiation dose and frequency, type and dose of first-line chemotherapy/chemo-immunotherapy, follow-up and staging outcomes with magnetic resonance imaging (MRI) [5,18–21]. Accordingly, while some studies suggest a clear survival benefit in patients receiving PCI, others support the idea that strict MRI-based follow up is actually superior to PCI [18–21]. Of note, PCI should be administered with caution because excessive radiation of certain areas in the brain may result in decline of one or more key domains of the cognitive functions [18–21]. Further studies are required to explore the potential of PCI in patients treated with chemo-immunotherapy and to clarify which patient populations should be treated with PCI or followed-up with MRI surveillance instead.
Although the vast majority of SCLC tumors are tantalizingly responsive to first-line chemotherapy, SCLC is characterized by a tumor recurrence rate of 90% . Radiation therapy as a local treatment approach is used both in case of limited- and extensive-stage disease, but there are considerable differences in its management protocols concerning the two groups. Specifically, concurrent radio-chemotherapy is part of the standard-of-care of patients with limited-stage disease, whereas radiotherapy in ES-SCLC mainly consists of cTRT after the first-line treatment [22▪].
CONSOLIDATION THORACIC RADIOTHERAPY IN PATIENTS WITH EXTENSIVE-STAGE SMALL CELL LUNG CANCER AFTER CHEMOTERAPY
Previous studies have shown that cTRT could improve the OS in chemotherapy-treated patients [22▪]. In their study, Jeremic et al. enrolled 210 individuals with ES-SCLC treated with cisplatin plus etoposide and evaluated the efficacy of radiotherapy. As for the study design, patients with complete response concerning their distant metastases received either thoracic radiotherapy with concurrent chemotherapy (TRT+CHT group) or were treated with additional chemotherapy (CHT group) only. The median OS was 17 vs. 11 months, whereas the 5-year OS rates were 9.1% vs. 3.7% in the TRT + CHT and CHT groups, respectively [20,22▪,23▪▪]. In the CREST multi-institutional phase 3 randomized study, a total of 495 patients were included who responded to initial chemotherapy and received subsequent PCI with or without TRT. Importantly, the 2-year OS rates were significantly higher in the TRT + PCI group (13%) compared to the PCI group (3%). Furthermore, in patients with residual intrathoracic disease, the OS was also significantly longer in TRT group [20,22▪,23▪▪]. In another randomized phase 2 trial (NRG Oncology RTOG 0937), the researches evaluated the 1-year OS in 97 ES-SCLC patients with intrathoracic disease and concomitant extracranial metastases. Although no significant improvements were achieved in the 1-year OS of cTRT-treated patients (vs. cTRT-naïve patients, median OSs were 13.8 vs. 15.8 months, respectively), cTRT resulted in prolonged disease control as compared to the control group (median PFSs were 4.9 vs. 2.9 months, respectively) [22▪,23▪▪]. Notably, according to a recent study, the time intervals and fractionations of TRT might as well have an impact on survival outcomes . Specifically, in this study on 492 ES-SCLC patients (out of which 244 received chemotherapy/thoracic radiotherapy) the OS, PFS and local recurrence-free survival (LRFS) were all improved in patients treated with CHT/TRT compared to those who received CHT alone (OS: 16.4 vs. 11.6 months, PFS: 7.9 vs. 6.5 months, LRFS: 10.6 vs. 7.1 months, respectively). Interestingly, patients who received 45 Gy at 1.5 Gy/fraction twice per day had significantly longer OS and PFS than those who received 60 Gy radiotherapy at 2 Gy/fraction on a daily basis (median OS: 22.7 vs. 18.2; median PFS: 11.3 vs. 9.3, respectively). Of note, the clinical outcomes were similar when comparing the patients in the hypofractionated radiotherapy group and the individuals in the conventional fractionated radiotherapy group . The results of these abovementioned clinical trials are summarized in Table 1.
Table 1 -
Consolidation thoracic radiotherapy in patients with ES-SCLC
|Jeremic et al. 1999 randomized phase 3 N = 109
||1. CRT + CHT + PCI 2. CHT + PCI
||54 Gy/36 fractions carboplatin/etoposide
||median OS: 17 ms vs. 11 ms 5-year survival: 9.1% vs. 3.7%
|Slotman et al. 2015 CREST trial randomized phase 3 N = 498
||1. cTRT + CHT + PCI 2. CHT + PCI
||30 Gy/10 fractions platinum/etoposide
||2-year OS: 13% vs. 3% 6-months PFS: 24% vs. 7%
|Gore et al. 2017 RTOG 0937 randomized phase 2 N = 97
||1. cTRT + CHT + PCI 2. CHT + PCI
||45 Gy/15 fractions platinum/etoposide
||1-year OS: 60.1% vs. 50.8%
|Han et al. 2021 N = 492
||1. TRT + CHT 2. CHT
||45 Gy/30 fractions platinum/etoposide
||OS: 16.4 ms vs. 11 ms PFS: 7.9 ms vs. 6.5 ms LRFS: 10.6 ms vs. 7.1 ms
|Diamond et al. 2021 retrospective study N = 22
||1. cTRT + CHT + IO
||30 Gy/10 fractions platinum/etoposide atezolizumab
||median OS: 16 ms low rates of toxicity
|Perez et al. 2021 prospective single-arm phase 1 and 2 N = 21
||1. cTRT + CHT + IO
||30 Gy/10 fractions platinum/etoposide ipilimumab, nivolumab
||median PFS: 4.5 ms median OS: 11.7 ms
|Galuba et al. 2021 retrospective study N = 33
||1.PCI/cTRT + CHT + IO 2. CHT + IO 3. PCI/cTRT + CHT
||cTRT + IO: no severe adverse event
CRT, consolidative radiotherapy; CHT, chemotherapy; cTRT, consolidative thoracic radiation therapy; IO, immunotherapy; LRFS, local recurrence-free survival, ms, months; OS, overall survival; PCI, prophylactic cranial irradiation; PFS, progression-free survival.
CONSOLIDATION THORACIC RADIOTHERAPY IN PATIENTS WITH EXTENSIVE-STAGE SMALL CELL LUNG CANCER TREATED WITH CHEMO-IMMUNOTHERAPY
Although the addition of atezolizumab, pembrolizumab and nivolumab to the standard-of-care platinum–etoposide backbone opened a new era in the clinical management of SCLC patients, limited data is available on the efficacy of cTRT in these patients [2,25]. This is mainly because general administration of cTRT was permitted nor in the IMpower133 or CASPIAN studies, neither in the KEYNOTE-604 trial [6▪]. Accordingly, only a few studies attempted so far to assess the role of cTRT and its antitumor activity in patients receiving immunotherapeutic agents. In a recent two-center retrospective study, Diamond et al. evaluated the efficacy and safety of cTRT (median dose: 30 Gy, median fraction number: 10) in a small cohort of twenty ES-SCLC patients treated with first-line platinum-based chemotherapy (carboplatin or cisplatin), etoposide and atezolizumab immunotherapy. Notably, none of the included patients received PCI. According to their results, cTRT appears to be well tolerated with low rates of toxicities, and the observed median OSs were comparable to the results of the modern clinical trials (CREST, IMpower133 and CASPIAN) [6▪,26▪▪]. Nevertheless, the exact association between OS and cTRT could not be predicted precisely due to the study's retrospective nature and the low number of included patients (Table 1) . Similar toxicity profiles were reported in a recent prospective single-arm phase 1/2 study . In this study, the researchers assessed the efficacy of cTRT (30 Gy in 10 fractions) after ipiliumab and nivolumab therapy, and found that the OS rate at 12-months was 48%. However, these promising results are slightly overshadowed by the relatively small sample size (n = 21; Table 1) . Lastly, it is worth mentioning that in a retrospective study of 33 patients, Galuba et al. also found that the rate of adverse events did not differ significantly between patients receiving both atezolizumab immunotherapy and TRT, and patients receiving TRT solely (Table 1).
CLINICAL PRACTICE GUIDELINES FOR CONSOLIDATION THORACIC RADIOTHERAPY
According to the contemporary ESMO Clinical Practice Guidelines, cTRT should be considered only in ES-SCLC patients with a PS of 0–1 when immunotherapy is contraindicated or in patients with a PS of ≥2 when positive response to chemotherapy was already achieved . Meanwhile, the NCCN Clinical Practice Guidelines in Oncology recommends sequential TRT only for well selected ES-SCLC patients who showed complete or partial response to systemic therapy. This applies especially to those with residual thoracic disease and low-bulk extrathoracic metastases . Besides, patients with vena cava superior syndrome, central airway compression, or atelectasis of the lung may also benefit from cTRT [6▪].
EFFECT OF CONSOLIDATION RADIOTHERAPY ON ANTI-TUMOR IMMUNE RESPONSE
Although SCLC tumors are usually associated with an immunosuppressive tumor immune microenvironment (TME), radiation therapy can enhance the antitumor immune responses . Specifically, radiotherapy upregulates both the tumor-associated antigens and Major Histocompatibility Complex (MHC) class I antigens, and promotes the CD8+ T cell-mediated killing of the tumor cells. Nevertheless, to date, no reliable biomarkers are available to predict this effect of radiation therapy on the tumor cells. Importantly, several studies suggest that combination of thoracic radiotherapy and immunotherapy exhibits a synergistic effect concerning the antitumor response since besides upregulating MHC class I expression and promoting CD8+ T cell infiltration, radiation also affects the TME through the release of tumor antigens and induction of the Cyclic GMP-AMP Synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway, upregulation of MHC class I expression, stimulation of type I interferons and promotion of CD8+ T cell infiltration [29,30]
Notably, the immunological landscape of the tumors also varies according to their neuroendocrine differentiation. SCLC tumors with high expression of neuroendocrine markers (SCLC-A and -N) are characterized by an “immune desert” phenotype and are, therefore, most likely resistant to immune checkpoint blockade. Meanwhile, tumors with low expression of neuroendocrine markers (SCLC-P and -Y/QN) are associated with increased immune cell infiltration (and “immune oasis” phenotype) which is one of the well known susceptibility features of immunotherapy efficacy [2,4,9].
Further large-scale prospective clinical trials are needed to determine the exact role of cTRT in patients treated with chemo-immunotherapy. Some of these have already started the patient enrollment and will likely provide valuable insights into the efficacy and safety of chemo-immuno-radiotherapy in ES-SCLC. Among others, the RAPTOR (NRG-LU005) trial investigates the efficacy of cTRT and atezolizumab immunotherapy as maintenance in patients treated with standard-of-care chemotherapy and atezolizumab [6▪,31]. Meanwhile, the PICARES study (NCT03971214) is a prospective pilot trial investigating the safety and efficacy of consolidation therapy in combination with a novel PD-1 inhibitor after standard chemo-radiotherapy. Notably, however, significant treatment-related adverse events were observed at the primary endpoints in this later study. In another phase 1 trial (NCT02402920), patients received pembrolizumab concurrently with thoracic irradiation after chemotherapy. No dose-limiting toxicities have been reported so far in this trial. The effects of consolidation ipilimumab and nivolumab therapy with subsequent radiotherapy were also investigated in the NCT03043599 trial, yet this study was recently interrupted due to the low PFS rates. NCT03923270 is an ongoing phase 1 study, in which the patients receive either durvalumab ± tremelimumab or olaparib concurrently with thoracic radiotherapy after chemotherapy with the aim of assessing the safety and efficacy of thoracic radiation in this setting. NCT03670056 on the other hand aims to examine the efficacy of ipilimumab and nivolumab after chemo-radiotherapy in recurrent ES-SCLC, whereas NCT03382561 is studying the clinical aspects of chemo-radiotherapy with concurrent nivolumab [26▪▪,32].
The synergistic effects of radiotherapy and immune checkpoint inhibitors on the TME and immune response represent a potential opportunity to improve the clinical outcomes of ES-SCLC patients. In general, contemporary guidelines suggest that cTRT is only recommended for well selected patients who respond to systemic therapy, with the aim of eradicating residual disease and improving local control. As for ES-SCLC patients treated with chemo-immunotherapy, cTRT might as well constitute an appealing treatment approach for those who have already responded to the initial systemic therapy and are in good general condition. Indeed, recent clinical trials suggest that cTRT contributes to prolonged survival and manageable toxicity profiles in these patients. Nevertheless, given that immunotherapy was just recently introduced in the therapeutic armamentarium of ES-SCLC, the efficacy of cTRT warrants further investigation in this setting. Therefore, until further large-scale prospective studies, cTRT should be administered with caution in ES-SCLC patients treated with chemo-immunotherapy. Indeed, recent trials suggest that cTRT contributes to prolonged survival and manageable toxicity profiles, yet further large-scale prospective studies are still needed to confirm these encouraging results. In addition, novel diagnostic and predictive biomarkers are also urgently needed for selecting the patients who will benefit the most from consolidation radiotherapy. Altogether, in the era of immunotherapy, radiation therapy represents an even more appealing treatment option for ES-SCLC patients than before, but the development of reliable predictors of the response is necessary for proper patient selection and treatment optimization.
The authors would like to thank Bence Ferencz for his assistance provided during the systematic literature search.
Financial support and sponsorship
B.D. was supported by the Austrian Science Fund (FWF I3522, FWF I3977 and I4677). Z.M. and B.D. acknowledge funding from the Hungarian National Research, Development and Innovation Office (KH130356 and KKP126790 to BD; “2020-1.1.6-JÖVO” and TKP2021-EGA-33 to B.D. and Z.M.). Z.M. was supported by the UNKP-20-3 and UNKP-21-3 New National Excellence Program of the Ministry for Innovation and Technology of Hungary, and by the Hungarian Respiratory Society (MPA #2020).
Conflicts of interest
There are no conflicts of interest.
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