Progress in radiotherapy for small-cell lung cancer

1 INTRODUCTION

Small-cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor accounting for approximately 15% of all lung cancers.¹ Despite sensitivity to radiotherapy, the prognosis of patients with SCLC remains poor, with a median survival of 15–20 months for limited-stage small-cell lung cancer (LS-SCLC), 8–14 months for extensive-stage small-cell lung cancer (ES-SCLC), and a 5-year survival rate of <7%.² The poor prognosis may be related to the high proliferation rate of SCLC tumors, early and extensive metastasis, and acquired chemoresistance.³

The treatment regimen for LS-SCLC has not changed over the years, the standard regimen including 4–6 cycles of cisplatin and etoposide chemotherapy (EP) combined with concurrent thoracic radiotherapy (TRT), and then prophylactic cranial irradiation (PCI)⁴ was conducted. In ES-SCLC, immune checkpoint inhibitors (ICIs) provides benefits, but is limited to early studies focusing on toxicity.⁵ Further studies are needed to improve the treatment regimen for SCLC and the survival rate of patients with SCLC. Therefore, we summarize new evolving therapeutic strategies (fractionation and dose, sequencing, and timing) and improved radiotherapy techniques (progress of PCI and SRS), and discuss the possibilities and prospects of combining radiotherapy with immunotherapy for SCLC.

2 TRT FOR LS-STAGE SCLC

To improve the efficacy of radiotherapy for SCLC, the Intergroup 0096 study developed a hyperfractionated radiotherapy (HFRT) regimen. This study demonstrated HFRT (45 Gy/30 fractions /1.5 Gy bid) was superior to daily radiotherapy (45 Gy/25 fractions /1.8 Gy qd).⁶ Overall survival (OS) significantly improved in the HFRT group, with the 5-year OS rate increasing from 16% to 26% (p = 0.04). Although the incidence of grade 3 radiation esophagitis was higher in the HFRT group than in the conventional fractionation group (27% vs. 11%, p < 0. 001), Intergroup 0096 was one of the few trials to demonstrate that changing the segmentation mode ultimately affects OS. However, this study was criticized for administering a lower dose of once-daily radiotherapy in the conventional fractionation group. Consequently, investigators have attempted to use a higher daily dose to assess whether once-daily higher-dose TRT is as effective as twice-daily TRT.

The CONVERT trial conducted in Canada compared the HFRT regimen (45 Gy/30 fractions /1.5 Gy bid) with a higher daily dose of conventional fractionation (66 Gy/33 fractions/2 Gy qd).⁷ The results showed that once-daily high-dose radiotherapy was not superior to 45 Gy HFRT. The median OS was 25 and 30 months (p = 0.14) and the 5-year survival rates were 31% and 34%, respectively. Although the risk ratio was higher for the twice-daily TRT, the difference was not statistically significant (p = 0.14). Therefore, HFRT should be continued as the standard regimen. In the C30610/RTOG-0538 trial, a further increase in dose to 70 Gy (70 Gy/35 fractions /2 Gy qd) was compared with the HFRT dose (45 Gy/30 fractions /1.5 Gy bid).⁸ Respectively, the median OS was 30.1 and 28.5 months (p = 0.594), respectively, and the 5-year survival rates were 32% and 29%, respectively. The frequency of serious adverse events (including esophageal and pulmonary toxicities) was similar between the two groups. The results of the 70 Gy cohort provide strong evidence in support of once-daily high-dose TRT in LS-SCLC.

It will be interesting to observe whether the benefits of HFRT in the higher dose group persist and whether the HFRT regimen significantly improved the OS in the Intergroup 0096 study, reaching a defined maximum tolerated dose of 45 Gy.⁶ As a result, a succession of investigators have attempted higher doses in hyperfractionation protocols. Hallqvist et al.⁹reviewed the use of Swedish hyperfractionation regimens from to 1998–2004, in which 46 patients were treated with a high-dose hyperfractionation regimen (60 Gy/40 fractions/1.5 Gy bid) and 34 patients were treated with a standard hyperfractionation regimen (45 Gy/30 fractions/1.5 Gy bid). The results showed that the local control rates were similar between the two groups (70% vs. 65%). The main adverse reaction was grade 3 acute radiation esophagitis, which occurred in 15% and 17% of patients in the two groups, respectively, with no statistically significant difference. Due to the design and sample size of this study, further research is needed to determine the clinical value of a high-dose hyperfractionation regimen. In contrast, a phase II trial in Norway showed a significant increase in the 2-year OS in the high-dose group (74. 2% vs 48. 1%) with higher dose of HFRT (60 Gy/40 fractions/1.5 Gy bid) compared to standard HFRT (45 Gy/30 fractions/1.5 Gy bid).¹⁰ The most common adverse effect was neutropenia (81% vs. 81%, p = 0. 25) and similar grade >3 radiation esophagitis (21% vs. 18%, p = 0. 83). A phase III clinical trial for this study is ongoing, and it will be interesting to observe whether the benefits of HFRT in the higher-dose group will persist.

Alternative approaches to improve the efficacy of TRT include studying the use of hypofractionated regimens (once-daily, higher-dose radiotherapy). A questionnaire containing 35 items showed that the most common dose and hypofractionated regimen was 40–45 Gy with 15 fractions (40%).¹¹ Evidence supporting the use of hypofractionation came from a phase II randomized trial with similar remission rates for the standard HFRT regimen (45 Gy/30 fractions/1.5 Gy bid) compared to the hypofractionation regimen (42 Gy/15 fractions/2.8 Gy qd) [qd:92% vs. bid:88%; p = 0.41].¹² Qiu et al. initiated a phase II trial comparing moderate hypofractionation (65 Gy/26 fractions/2.5 Gy qd) with standard HFRT (45 Gy/30 fractions/1.5 Gy bid). Moderate hypofractionation showed improved progression-free survival (PFS) in patients compared with twice-daily hypofractionation (2-year PFS rate: 42.3% vs. 28.4%). Most toxicities had similar incidences in both groups; however, the once-daily group had higher incidence of grade ≥3 acute lymphopenia (71.7% vs. 40.2%; p < 0.001).¹³ Data from the National Cancer Database,^14-16 suggest that hypofractionated radiation does not appear to be worse than standard radiotherapy. Furthermore, in a meta-analysis based on the latest pooled phase II trial,¹⁷ hypofractionated radiotherapy was associated with an improvement in OS compared to HFRT (p = 0.03). Additional randomized phase III trials are required to explore the efficacy of hypofractionated radiotherapy.

Current data suggest that the HFRT regimen (45 Gy/30 fractions/1.5 Gy bid) should be the the standard regimen for TRT in LS-SCLC. If this is not possible for logistical or resource reasons, conventional fractionated regimens (60–70 Gy/30–35 fractions/2 Gy qd) are recommended. For patients who have a poor baseline status or significant comorbidities, a hypofractionation regimen (40–45 Gy/15 fractions qd) is reasonable.¹⁸

The Japanese Clinical Oncology Group (JCOG 9104)¹⁹ performed a phase III study to compare the efficacy of concurrent radiotherapy with sequential radiotherapy (chemotherapy followed by radiotherapy) in patients with LS-SCLC. The results showed that patients treated with concurrent radiotherapy had better OS at 2, 3, and 5 years than those in the sequential treatment group (2-year OS: 54.4% vs. 35.1%; 3-year OS: 29.8% vs. 20.2%; 5-year OS: 23.7% vs. 18.3%), although the difference was not statistically significant (p = 0.097). The disadvantage of sequential therapy over concurrent therapy is the development of resistant tumor clones after systemic therapy, which are often resistant to radiotherapy and lead to tumor repopulation.²⁰ In addition, He et al.²¹ showed that concurrent chemoradiotherapy OS was superior to that of sequential therapy, with a manageable toxic response. Therefore, the results of this study indicated that concurrent therapy is currently the standard treatment regimen for LS-SCLC.⁴

The debate on the optimal timing of radiotherapy for LS-SCLC has not been fully resolved, and has been a hot topic in several recent studies. Perry et al.²² reported on the CALGB 8083 study supporting late TRT. The study involved 399 patients with LS-SCLC randomised to TRT beginning on day 1 (early TRT) or day 64 (late TRT) after chemotherapy, and showed that the median overall survival (mOS) of patients with late TRT was superior to that of the early radiotherapy group (14.54 vs. 13.04 months, p = 0.0072). In addition, Bayman et al.²³ evaluated the effect of 1–2 cycles of chemotherapy after (early TRT) and 3–6 cycles of chemotherapy after (late TRT) on the survival rates of patients with LS-SCLC. A retrospective analysis of 70 patients with SCLC treated with radiotherapy revealed that the 3-year OS rate was better with late TRT (31%) than with early TRT (17%). In contrast, Murray et al.²⁴ reported the findings of a randomised study performed by the Clinical Trials Group of the National Cancer Institute of Canada, which enrolled 155 patients who received early TRT (beginning on day 22) and 153 patients who received advanced TRT (beginning on day 106). The 3-year OS rates (29.7% vs. 21.5%, p = 0.006) and mOS (21.2 vs. 16 months, p = 0.008) were significantly better with early radiotherapy than with late radiotherapy.²⁴ However, in a phase III trial, Sun et al.²⁵investigated the use of TRT concurrent with cycle one or three chemotherapy in LS-SCLC with a TRT dose of 52.5 Gy/2.1 Gy and showed no significant difference in mOS (24.1 vs. 26.8 months) and PFS (12.4 vs. 11.2 months) between the early and late TRT groups.

Several key points should be considered when interpreting the results of studies on the timing. The definitions of TRT timing, chemotherapy regimens, adherence, and patient selection criteria require a thorough analysis of relevant study results.²⁶ Johannesma et al.²⁷ reported no statistically significant differences in the 2-year OS rates of patients (p = 0.18). When only trials using platinum-based chemotherapy with concomitant chest radiotherapy were considered, statistically significant 2- and 5-year OS rates were observed when chest radiotherapy was initiated within 2 d of chemotherapy (2-year OS rate, p = 0.01; 5-year OS rate, p = 0.02). Ruysscher et al.²⁸ performed a meta-analysis of nine randomized trials involving 2305 patients. No difference in OS was found between earlier (before chemotherapy cycle 3) and later radiotherapy. However, early TRT was beneficial when trials with similar proportions of chemotherapy adherence were analyzed. Although the incidence of acute esophagitis²⁸ was higher, the 3- and 5-year survival rates with early radiotherapy increased by 5.7% and 7.7%, respectively.

Although the optimal timing of radiotherapy in LS-SCLC remains controversial, most guidelines and practice patterns recommend early TRT (starting from the first or second cycle of chemotherapy).^28-30 This may be because early TRT allows the exploitation of the synergistic effect of radiotherapy and eliminates as many tumor cells as possible in a shorter period by reducing the time to the formation of resistant tumor clones after chemotherapy. However, later TRT is an option in some cases. For example, if the primary tumor is large, it is recommended that clinicians extend the chemotherapy time to reduce the tumor size and increase radiation therapy, as well as to increase the cytotoxicity caused by chemotherapy and the unacceptable toxicity caused by the earlier combination of TRT. Particularly, for elderly patients who are concerned regarding the toxicity of concurrent therapy, a sequential treatment approach may be more beneficial.

3 ROLE OF SBRT IN STAGE I OR II NODE NEGATIVE SCLC

The efficacy of SBRT has been widely recognized in non-small-cell lung cancer (NSCLC) due to a high local control rate and extremely short treatment time, making it popular for early stage NSCLC.³¹ Based on the success of SBRT for NSCLC, researchers have begun to evaluate its efficacy in SCLC. The characteristic hypofractionated pattern of SBRT can inhibit tumor cell regeneration or induce apoptosis, achieving the goal of eliminating all tumor cells in the target volume.³² Previous retrospective clinical studies have shown that patients with stageI–IIA SCLC and negative lymph nodes confirmed by mediastinoscopy have better survival rates after surgical resection.^33-35 However, 69% of the eligible population did not undergo surgery because of specific limitations such as advanced age, cardiopulmonary function, and tumor location.³⁶ The optimal treatment strategy for LS-SCLC, especially stage I–IIA SCLC, remains to be explored. Recent studies have found that SBRT has achieved encouraging results in patients with stageI–IIA SCLC. Many clinical studies using SBRT have reported excellent local control rates, especially in early stage SCLC.^37-41

Shioyama et al.³⁷ collected data from 269 patients with lung cancer undergoing SBRT in Japan from 2004 and 2009. Among them, eight patients with stage I SCLC who were inoperable (75%) or refused surgery (25%) were selected as research subjects. The survival outcomes of patients with stage I SCLC who received SBRT were analyzed for the first time. Patients with clinical stage I SCLC achieved positive outcomes when treated with SBRT of 48 Gy in four fractions, combined with chemotherapy or not; the 3-year survival rate was 72%, and local control rate was 100%. As no level 2 or higher toxicity was observed, this treatment was considered well tolerated.³⁷ Subsequently, he updated his research results twice, in 2015 and in 2018. In 2015, the number of patients increased to 64, and the average radiotherapy plan remained at 48 Gy in 4 fractions (BED 10 Gy = 105.6 Gy). The 2-year OS and cancer specific survival (CSS) rates were 76.3% and 79.1%, respectively. However, the 2-year PFS and LCR were 49.3% and 89.3%, respectively, and adverse reactions were limited to grade 1–2.⁴⁰ In the latest study published in 2018, 43 patients with stageISCLC were included, of which 79% were inoperable, and the proportion of positron emission tomography-computed tomography (PET-CT) staging was further reduced to 29.7%.³⁸ The 2-year OS, PFS, and LCR rates were 72.3%, 44.6%, and 80.2%, respectively. The incidence of radiation toxicity in this study was slightly higher than that in the two previous studies, and grade 3 radiation pneumonitis (4.7%) was observed. The results of this study were similar to those of the two previous studies, but with a larger sample size, multi-institution data, and higher reliability. Therefore, SBRT is a secure and efficient treatment choice for individuals diagnosed with stage I or II SCLC.

In addition, two studies from the United States were similar and included six and eight patients with stage I SCLC. The proportion of chemotherapy was approximately 60%, although the radiotherapy fractionation scheme was slightly different, but the BED 10 Gy was ≥100 Gy. The adverse effects were mild in these two studies, with 1-year OS rates of 63% and 87.5% and LCR rates as high as 100%.^{39, 41} Among them, Ly et al.³⁹ achieved a median survival of 22 months after SBRT treatment of such patients for the first time. Researchers from the Third Military Medical University have reported the prognostic data of SBRT for patients with LS-SCLC in China. Among the 29 patients, only four (14%) were stage I, whereas the other patients were stage II (28%) and stage III (58%). The prescribed SBRT was 40–45 Gy in 10 fractions.³⁰ Due to the large number of patients with stage II–III disease and an insufficient BED dose of 10 Gy (56–65 Gy), the 2-year OS, PFS, and LCR rates in this study were lower than those in similar studies (47.7, 27, and 55.2%, respectively). Surprisingly, the median survival in this study was not significantly affected at 27 months, possibly due to the use of standard chemotherapy and PCI.

Currently, surgery alone or surgery combined with chemotherapy is recommended for patients with node-negative T1–T2 SCLC. SBRT can deliver very high radiation doses to tumor tissues and achieve the best protection of normal tissues to complete the targeted killing of the tumor, which has great commonality with surgery in the local treatment of tumors. To this end, we compared recent studies of surgery for early-stage SCLC with the aforementioned studies of SBRT. In the study by Weksler et al.³⁵, 895 patients with stage I or II SCLC who underwent surgery had a 5-year OS of 26.8% and a median survival of 34 months. In a study by Yu et al.⁴², the 3- and 5-year OS rates in 205 patients with stage I SCLC who underwent surgical treatment were 58% and 50%, respectively, and the median survival was approximately 60 months. However, in a new study by Yang et al.⁴³, the 3- and 5-year OS rates of 681 patients with node-negative T1–T2 SCLC who underwent surgical treatment were 60% and 48%, respectively, with a median survival of approximately 55 months. In fact, numerous meta-analyses have confirmed that the 5-year OS of patients with stage I SCLC undergoing surgical treatment fluctuates between 40% and 60%, which is superior to SBRT in terms of long-term survival; however, the results were similar in terms of 3-year OS rate.^44-46 Notably, the median age of patients receiving SBRT was significantly higher, and chemotherapy and PCI were not properly performed due to aging and comorbidities. Simultaneously, the majority of patients did not undergo PET-CT staging at the mediastinal pathological stage, which may have led to confusion with patients with positive mediastinal lymph nodes. Therefore, it is reassuring that SBRT can achieve a 3-year OS similar to that of surgery. At present, the controversy regarding SBRT for SCLC comes mainly from two aspects. Due to the lack of preventive radiation for regional lymph nodes in SBRT, there is a risk of recurrence if the mediastinal lymph nodes have subclinical metastases.⁴⁷ However, even in patients treated with standard systemic chemotherapy, the pattern of failure of SBRT is dominated by distant metastasis (20%–51%) rather than nodal recurrence (0–28%). Therefore, it is particularly important to popularize PET-CT to guide the staging of the initial diagnosis and reasonably screen inoperable stage I patients. However, high-dose and hypofractionated regimens are limited by technical limitations and lack of experience, which can aggravate esophageal and lung injuries. The current studies were all conducted in research centers with good technical teams, and adverse reactions were well controlled. Most studies have shown that grade 3 adverse reactions to SBRT for early stage SCLC are rare (0–6.9%). Therefore, it is necessary to carefully consider the need for experienced clinical teams and reasonable radiation plan.⁴⁷

4 PROGRESS OF PCI AND SRS

ES-SCLC accounts for the majority of patients with SCLC (60%–70%), and a phase III trial by Slotman et al.⁴⁸ confirmed the effectiveness of PCI in patients with ES-SCLC who had a positive response to chemotherapy. The landmark EORTC trial showed that a significantly lower risk of brain metastases in the PCI group (14.6% vs. 40.4%, p < 0.001). The mOS was significantly better in the PCI group (6.7 vs 5.4 months; p = 0.003). However, only 29% of participants were scnned in the brain prior to randomization. Therefore, asymptomatic yet radiologically detectable brain metastases could be included in the EORTC trial and contribute to the positive results.⁴⁹ Subsequently, a Japanese phase III randomized trial compared PCI and magnetic resonance imaging (MRI) monitoring in 224 patients and required brain MRI evaluation before recruitment and after follow-up, which ensured detectable brain metastases and the timely detection of brain metastasis progression.⁵⁰ Patients with ES-SCLC who did not have brain metastases confirmed by MRI did not experience a statistically significant increase in OS with the use of PCI (p = 0.094). However, PCI reduced the risk of brain metastases by 26% at 1-year follow-up. Notably, 83% of the patients in the control group who developed brain metastases received remedial brain radiotherapy compared to 60% in the EORTC trial. Keller et al.⁵¹ showed that MRI screening after chemotherapy is important because almost 16% of patients who are chemotherapy-responsive were detected unsuspected brain metastases. PCI reduced brain metastases with no significant effect on OS in the MRI screening era. These results suggest that timely detection of brain metastases using brain MRI increases the chances of patients receiving remedial radiotherapy, thereby improving survival. Therefore, MRI monitoring and timely remedial radiotherapy in patients with ES-SCLC can eliminate PCI, which is an acceptable option in the absence of brain MRI or MRI monitoring.⁵²

Immunotherapy has become the standard regimen for treating ES-SCLC since the CASPIAN and IMPower 133 trials were published. However, data on PCI are limited, and the role of PCI in immunotherapy is unclear. Only 11% of patients in each arm of the Impower 133 study underwent PCI.⁵³ In the CASPIAN study, PCI was allowed only in the control group.⁵⁴ Analysis of the CASPIAN and IMpower 133 studies showed that the Durvalumab or Atezolizumab combination chemotherapy group had a delayed time to brain metastasis compared with the control group (RR:0.69 vs 0.72). These results suggested that immunotherapy may delay or even prevent the formation of brain metastases in individuals with ES-SCLC.^{55, 56} As immune checkpoint inhibitors (ICIs) improve disease control and prolong OS in ES-SCLC, PCI may become more important for controlling central nervous system (CNS) diseases. In contrast, ICIs are capable of stimulating T cells peripherally to, in turn, have antitumoral effects in the CNS, thus diluting the benefit of PCI or even whole-brain radiotherapy.^{49, 57}

The results of multiple meta-analyses^58-60 established PCI as the standard of regimen for LS-SCLC. Auperin et al.⁵⁹ analyzed the data of 987 patients in seven randomized trials. They found a 5.4% overall improvement in OS at 3 years and a significant 25.3% decrease in the occurence of brain metastases at 3 years. Meert et al.⁶⁰ confirmed the role of PCI in a meta-analysis of 12 randomized studies. However, the studies included in these meta-analyses were conducted in an era when brain MRI was not widely available, and CT scans were significantly less likely to confirm brain metastases than MRI scans, which may have allowed some patients with asymptomatic brain metastases to be treated with PCI, thus influencing the trial results. Several retrospective studies^61-63 did not find a significant benefit of brain MRI at diagnosis or before PCI on OS in patients with LS-SCLC. Pezzi et al.⁶⁴ retrospectively analyzed 297 cases of LS-SCLC in good remission after radiotherapy, and routine cranial MRI was performed to exclude brain metastases both at the assessment of staging and before PCI; they showed that the 3-year brain metastasis rates were 11.2% and 20.4% in the PCI and control groups (p = 0.10), with no difference in any of the 3-year survival comparisons. These findings suggest that brain MRI should be performed prior to PCI to identify asymptomatic patients with brain metastases and to administer appropriate doses of brain radiotherapy to these patients. Of course, these studies were retrospective analyses, and the small sample size may have affected the final study results. Several phase III clinical trials (such as NCT04155034 and MAVERICK) are currently underway to explore the value of PCI in LS-SCLC in the era of MRI, and the results of these clinical trials are promising.^{65, 66}

The survival benefit of PCI comes at the cost of increased neurocognitive toxicity, and several previous studies have shown that neurocognitive decline may occur after PCI treatment.^67-69 Clinical studies have shown that the dentate gyrus in the hippocampal region of the skull is where most neuronal stem cells accumulate, and that neurocognitive dysfunction after PCI is closely associated with radiation damage to the hippocampus.^{70, 71} A recent study using PET-CT to observe brain metabolism before and after PCI showed that PCI significantly reduced brain metabolism, whereas a technique referred to as hippocampal-avoidance prophylactic cranial irradiation (HA-PCI) preserved the metabolic activity of the hippocampus.⁷² The results of several studies have shown that metastases in the hippocampus account for a low incidence of all brain metastases (0.4%–3.3%).^73-75 Therefore, HA-PCI has become an attractive technique. The results from the NRG CC001 and RTOG0933 studies demonstrated that HA-WBRT is associated with neurocognitive function.^{76, 77} However, the efficacy of HA-PCI for SCLC remains unclear. Vees et al. initiated a multicenter phase II trial to evaluate the impact of HA-PCI in patients with LS-SCLC, and the results suggested that HA-PCI was a viable option.⁷⁸ The results of two phase III trials (PREMER RCT and NCT01780675) in 2021 showed significant improvements in neurocognitive function in the HA-PCI group, and both trials found no significant differences in OS and brain metastasis rates between the HA-PCI and PCI groups.^{79, 80} These clinical trials suggest that HA-PCI can be used as an alternative to conventional PCI or MRI monitoring, and that preserving the hippocampus during PCI can better preserve cognitive function in patients with SCLC. However, caution is needed regarding the risk of perihippocampal brain metastases after PCI, and a larger sample size in phase III clinical trials is required to validate the efficacy and safety of HA-PCI.

Although WBRT has shown an OS benefit, it causes lacrimal and parotid gland dysfunction, leading to a decreased quality of life. Even with HA-WBRT, a decline in relevant cognitive domains (executive function, learning, and memory) has been observed in up to 51.2% of patients.^{77, 81, 82} Patients receiving SRS vs. WBRT reported better posttreatment health-related quality of life (hrQoL), in addition, dosimetric analyses of multilesion SRS suggests that SRS may be potentially the most effective strategy for avoiding the hippocampal and normal brain tissues.^{83, 84} FIRE-SCLC Cohort Study showed an improvement in OS (median, 6.5 months for SRS vs. 5.2 months for WBRT; p = 0.003).⁸⁵ Furthermore, nine observational studies with 1638 patients were included, and the meta-analysis showed a favorable outcome for local control and OS in highly selected patients with SRS.⁸⁶ SRS is the first-line treatment option for patients with SCLC brain metastases.

5 cTRT FOR ES-SCLC

Three randomized studies evaluated the safety and efficacy of consolidative thoracic radiation therapy (cTRT) after chemotherapy in patients with ES-SCLC. cTRT after first-line platinum-etoposide therapy in the CREST phase III randomized trial did not result in the improvement in the 1-year OS rate in the overall population (n = 495). However, in a predetermined investigation, the patients who received consolidation radiotherapy to the chest experienced a significantly greater 2-year OS (13% and 3%, respectively; p = 0.004).⁸⁷ Jeremic et al. conducted a study to randomly assigned patients with a complete response to external thoracic metastases after three cycles of cisplatin-etoposide to cTRT with cisplatin-etoposide group or cisplatin-etoposide alone group. The cTRT group had a better median OS (17 vs. 11 months, p < 0.05) and 5-year local recurrence-free survival (20% vs. 8.1%, p < 0.06) with the increase of grade 3 toxicities, such as esophagitis.⁸⁸ The RTOG 0937, a randomized phase II trial assessing the effect of PCI or PCI+cTRT on 1-year OS in extracranial metastases of ES-SCLC, showed that cTRT slowed progression, the 3- and 12-month rates of progression were 53.3% and 79.6% for PCI and 14.5% and 75% for PCI+cTRT, respectively. However, there was no improvement in 1-year OS.⁸⁹ In a meta-analysis of these three studies, consolidation radiotherapy to the chest improved the PFS (p < 0.0001).⁹⁰ Therefore, consolidation radiotherapy may be considered for patients with ES-SCLC who show a partial response and maintain their functional status after first-line platinum-based chemotherapy.

The data on the role of cTRT in ES-SCLC are limited in the immunotherapy era. This is mainly because the use of conventional cTRT was not allowed in the IMpower133, CASPIAN, or KEYNOTE-604 trials.⁹¹ Limited investigations into the impact of cTRT and its effectiveness against tumors in patients who have undergone immunotherapy. In a recent study conducted by Diamond et al., the effectiveness and safety of cTRT were assessed in 20 patients with ES-SCLC who received first-line chemotherapy and atezolizumab immunotherapy. The results showed that cTRT was well tolerated, with a low incidence of toxicity, and the median survival rate observed was consistent with the results of modern clinical trials (CREST, IMpower133, and CASPIAN).^{91, 92} The toxicity profile of a recently prospective single-arm phase I/II study was similar to that reported in the previous study.⁹³ Researchers in this study assessed the effectiveness of cTRT (30 Gy/10 fractions) following ipilimumab and nivolumab treatment and the results showed that the 1-year OS rate was 48%.⁹³ Limited data are available on the true role of chest consolidation radiotherapy in the immunotherapy era, and further studies are required to evaluate the safety and effectiveness of this methods in patients with ES-SCLC.

Sequential TRT was recommended only for carefully selected patients with ES-SCLC who demonstrated a complete or partial response to systemic therapy, according to the NCCN Clinical Practice Guidelines for Oncology. This is particularly true for patients who have remaining chest disease and low-volume metastases outside of the chest.¹ Furthermore, in accordance with contemporary ESMO clinical practice guidelines, cTRT should only be taken into account in ES-SCLC patients with PS 0–1 and contraindication to immunotherapy, or patients with PS 2 and a positive response to chemotherapy.⁹⁴ In addition, patients with superior vena cava syndrome, central airway compression, or atelectasis may benefit from cTRT.⁹⁵

6 RADIOTHERAPY-IMMUNOTHERAPY WITH ICIS FOR THE TREATMENT OF SCLC

The combination of radiotherapy and immunotherapy shows potential as a treatment option for difficult-to-treat malignant tumors like SCLC. Radiotherapy enhances synchronized immune stimulation at the tumor site, transforming non-transient immune responses into effective and durable immune responses.⁹⁶ Despite immunosuppression and cytotoxicity, radiotherapy-immunotherapy enhances the body's response.^{97, 98} In NSCLC, radiotherapy-immunotherapy significantly improves disease control rates and prolongs median PFS and OS.^99-102 However, the efficacy of radiotherapy-immunotherapy for SCLC has not been fully elucidated.

Since CASPIAN and IMpower 133 trials were published, immunotherapy has ushered in a new era in the clinical treatment of patients with ES-SCLC; however, data on the efficacy of TRT in patients with ES-SCLC are limited and confined to early studies of ES-SCLC toxicity.^{103, 104} This is mainly because neither the IMpower 133 or CASPIAN studies nor the KEYNOTE-604 trial allowed the use of TRT.⁹¹ In a single-arm phaseItrial (NCT02402920), Welsh et al. evaluated the safety of combining pembrolizumab with TRT (45 Gy in 15 fractions) after induction chemotherapy in patients with ES-SCLC.¹⁰⁵ The results showed that the concomitant use of pembrolizumab with TRT was well tolerated, with few high-grade adverse events in the short-term. An additional prospective single-arm phase I/II study (NCT03043599) showed that after chemotherapy for ES-SCLC, ipilimumab and nivolumab in combination with TRT (consolidative TRT to 30 Gy in 10 fractions) resulted in a 61.9% incidence of grade 3–5 adverse events (AEs) and a 52.4% incidence of immune-related adverse events (irAEs).⁹³ This study demonstrated an increase in toxicity. This study showed increased toxicity, possibly due to the treatment administered after platinum-based doublet chemotherapy. CHECKMATE-451 had a similar study design without TRT, and showed a similar toxicity profile in the ipilimumab or nivolumab study arm as NCT03043599.¹⁰⁶ NCT03043599 study demonstrated the feasibility of delivering 30 Gy consolidating TRT with ipilimumab or nivolumab. Diamond et al. performed a two-center retrospective study¹⁰⁷ to assess the effectiveness and safety of cTRT (median dose:30 Gy) in 20 patients with ES-SCLC treated with first-line platinum-based chemotherapy (carboplatin or cisplatin), Etoposide and Atezolizumab immunotherapy. The results showed that cTRT was well tolerated, had a low toxicology rate, and that the observed mOS was consistent with the results of published modern clinical trials (IMpower133 and CASPIAN). Because the sample size is small, more research is necessary to determine if cTRT still offers survival advantages in the era of immunotherapy.

Although ICIs are not authorized for use in LS-SCLC, triple therapy with programmed death ligand 1 (PD-Ll) therapies (such as Atezolizumab or Durvalumab) in combination with EP is the standard regimen for ES-SCLC.^{53, 54} It remains unclear whether adding ICIs to CCRT yields similar benefits. Therefore, we reviewed the safety and effectiveness of ICIs combined with CCRT and the current clinical trials that are investigating novel new treatments for LS-SCLC. In 2015, Welsh et al.¹⁰⁸ initiated a phase I/II trial of CCRT combined with pembrolizumab (NCT02402920). This trial demonstrated the safety and efficacy of combining ICI and CCRT in patients with LS-SCLC. The trial enrolled 40 patients, with grade 4 AEs occurring in three patients (two patients with neutropenia and one patient with respiratory failure). The most common grade 3 toxicities were neutropenia and anemia, both of which were reported in five patients. In addition, the analysis showed favorable OS and PFS results in this trial compared with the CONVERT trial (OS: 39.5 vs. 30 months; PFS: 19.7 vs. 15.4 months), with a higher 2-year OS rates (65.8% vs. 56%). However, the small sample size and relatively short follow-up period of this phaseI/II trial limited its ability to assess the effectiveness of pemrolizumab in combination with radiotherapy. Additionally, Peters et al.¹⁰⁹ initiated a randomized multicenter phase II trial of nabolutumab and ipilimumab in combination with radiotherapy, in addition to PCI for consolidation. The percentage of patients with grade ≥3 AEs of any cause was 61.5% in the experimental group (51.3% of patients with treatment-related AEs) and 25.3% in the observation group. The mPFS between the experimental and control groups (10.7 vs. 14.5 months) was not statistically significant (p = 0.93), whereas mOS was not reached in the experimental group and 32.1 months in the observation group (p = 0.82). This illustrates the toxicity of short periods of active treatment and treatment interruptions, which may affect efficacy outcomes. The safety of TRT immunotherapy in early-stage trials has encouraged prospective trials currently under way. The safety and effectiveness of CCRT in combination with ICI (single or multi-drug combination) for the treatment of patients with LS-SCLC are being investigated in ongoing prospective trials (NCT03540420, NCT03703297, and NCT04308785).

Although there is a growing consensus that ICIs in combination with radiotherapy can improve response rates, this approach may be subject to persistent radiation-induced immunosuppression.¹⁰⁹ To achieve a more sustained immune response and enable monitoring of individualized therapeutic approaches, it is critical to assess the dynamics of the immune system at the patient level and develop biomarkers.¹¹⁰ Tumor mutation burden (TMB), PD-L1, tumor-infiltrating lymphocytes (TILs), and circulating tumor cells (CTCs) are important biomarkers for SCLC immunotherapy.¹¹¹ Only 18%–32% of patients with SCLC exhibit PD-L1 expression, 95% of patients have a PD-L1 tumor percentage score (TPS) of less than 1%, and PD-L1 and survival index.⁵⁴ There was no correlation between PD-L1 expression and survival index. Studies have shown that higher TMB levels are associated with higher OS and PFS, and SCLC is the TMB high solid tumor type.¹¹² SCLC is found to have a more immunosuppressive tumor microenvironment (TME) over NSCLC.¹¹³ The tumor microenvironment, which includes infiltrating T cells, tumor-associated macrophages, and cancer-associated fibroblasts, is also important for assessing the response to radiotherapy-immunotherapy. Patients with SCLC and more TILs have a better prognosis before immunotherapy.^114-117 Studies have shown that an increase in the number of CTCs predicts poor immunotherapy outcomes.^{118, 119} Therefore, biomarkers should be emphasized to better assess the immune status before radiotherapy-immunotherapy is initiated. In addition, recent proton therapy studies have shown that intensity-modulated proton radiotherapy (IMPT) has additional energy degrees of freedom compared to IMRT, with the potential to achieve a significant reduction in radiation-induced lymphopenia without compromising the dosimetric constraints of standard tumor and normal tissue.¹²⁰ Since the effectiveness of immunotherapy depends on the health of the immune system, the benefit would be greater with immunotherapy after IMPT than with IMRT.

7 CONCLUSION

Radiotherapy remains the mainstay treatment for SCLC, with combination immunotherapy as a new modality. TRT improves the OS of patients with SCLC, and most guidelines and practices recommend early TRT (starting with the first or second cycle of chemotherapy). HFRT (45 Gy/30 fractions/1.5 Gy bid) is the standard regimen for TRT in LS-SCLC. In some cases, conventional fractionation regimens (60–70 Gy/30–35 fractions/2 Gy qd) and hypofractionation regimens (40–45 Gy/15 fractions qd) are reasonable. SBRT has excellent local control rates and can be a safe and effective treatment option for stage I or II SCLC. TRT with timely remedial radiotherapy in patients with ES-SCLC can eliminate PCI. To better preserve cognitive function in patients with SCLC, HA-PCI can be used as an alternative to conventional PCI or MRI surveillance, and it is necessary to monitor for metastasis or recurrence in the peripheral area of the hippocampus. SRS is supported as a treatment option for patients with SCLC with brain metastases. The safety and efficacy of cTRT have been evaluated in patients with ES-SCLC, and further studies with larger sample size are required. In NSCLC, radiotherapy-immunotherapy significantly improves disease control rates. However, the safety and efficacy of radiotherapy-immunotherapy in patients with SCLC have not been fully elucidated, and in connection with larger toxic effects, caution should be taken in future studies to avoid severe toxicity. Future research should consider the exploration of radiobiology research directions, such as unconventional fractionation and hypofractionated regimens, to change the immune microenvironment of SCLC and improve the overall efficacy. Further studies are required to explore the means to reduce radiation-induced lung injury and immunotoxicity and to improve the safety and efficacy of combined therapy.

CONFLICTS OF INTEREST STATEMENT

The authors declare that there are no conflicts of interest to disclose.

ETHICS STATEMENT

The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. We guarantee that this manuscript has not been published elsewhere and is not under consideration by any other journal. All authors have approved the manuscript and agreed with submission to Precision Radiation Oncology.