The combination of chemotherapy and immunotherapy has been new treatment standard for ES-SCLC after decades without a change based on the etoposide with platinum chemotherapy [14]. The OS has been approximately prolonged 2 months with the combination of PD-L1 inhibitors and chemotherapy [7, 15]. However, in these studies, consolidative TRT was not designed. The number of patients who received palliative TRT was very low and no unexpected adverse events were observed. Thus, in the era of immunotherapy, the role of TRT in ES-SCLC is still unclear.
Approximately 75% of ES-SCLC patients have intrathoracic residual after chemotherapy [5, 16]. The CREST trial reported consolidative TRT could improve the outcome for ES-SCLC with intrathoracic residual after first line chemotherapy. Furthermore, it is also reported an almost 50% reduction in intrathoracic recurrence [5]. In IMpower 133 trial, approximately 80% of patients had lung or thoracic lymph node involvement. As only 2.5% of patients experienced a complete response after atezolizumab plus chemotherapy. Thus, the locoregional treatment may further improve outcomes in this population.
In our study, TRT group significantly prolonged OS, PFS and LRFS. Compared with no TRT, the OS at 1 year in TRT group improved 10% (71.2% vs 61.5%). And the 1-year OS in no TRT group was consistent with the data of recent ASTRUM 005 trial reported [17]. In addition, the PFS at 6 months increased from 31.6–64.1% after TRT. And the PFS at 6 months in no TRT group was consistent with the data reported in IMpower 133 trial [18], suggesting that our findings are representative and applicable to patients with ES-SCLC. In the further analysis of CREST trial, the results showed that patients with non-liver metastasis or less distant metastases could benefit more from consolidative TRT [6]. Several studies have demonstrated oligo-metastatic ES-SCLC without brain and liver metastasis could benefit more from TRT [19, 20]. In our study, TRT significantly improved LRFS and PFS foe ES-SCLC with oligo-metastasis and without liver metastasis subgroup. This trend persisted after PSM. However, there was no significant difference of OS in oligo-metastasis and non-liver metastasis subgroup, which need large scale population to confirm the OS benefit from TRT.
TRT was well tolerated and no severe toxic effects were recorded in our study. There were no randomized data reporting the safety of TRT in ES-SCLC after immunotherapy. Welsh et al. reported the good safety of concurrent pembrolizumab and TRT, with no grade 4–5 toxic events [21]. Another retrospective study also demonstrated the relative safety for consolidation TRT after atezolizumab [22]. Notably, RAPTOR/NRG LU-007 is an ongoing randomized trial to study the efficacy and safety of RT for ES-SCLC patients after atezolizumab plus chemotherapy (NCT 04402778). In our study, the radiation dose was delivered heterogeneously according to the intrathoracic residual. The radiation dose for the ES-SCLC is also debatable, which need more studies to illustrate.
In addition, the safety and efficacy of prophylactic cranial irradiation (PCI) for ES-SCLC after immunotherapy has not yet been defined and need further studies. In our study, only 3 patients underwent PCI without cranial progression and central nervous system-related events during follow up. But there were 19 of 95 progression patients have developed cranial metastasis after immunotherapy plus chemotherapy. In IMpower 133 trial, central nervous system-related events has been evaluated in 22 patients who received PCI, appeared to be more common in the atezolizumab group.
There were several limitations in our study. This was a retrospective study with limited number of patients and the patient population and thoracic radiation dose was not consistent. Although, the PSM analysis was used to decrease the baseline characteristics difference in both groups, prospective randomized trials are in great urgency to confirm the role of TRT for ES-SCLC in the era of immunotherapy.