Our study indicated that TRT significantly improved LRFS compared to that receiving chemo-immunotherapy only but failed to prolong the PFS and OS. Further subgroup analyses indicated that TRT had a trend of survival benefits in patients with brain metastases. In addition, TRT-induced RIP was also acceptable while no grade ≥ 4 pulmonary toxicities occurred. Regardless of no benefits of TRT on survival, TRT was still a potentially potent strategy for ES-SCLC due to the possibility of remarkable LRFS translating into survival benefits in selected settings.
The magnitude of survival benefit seen with consolidative TRT in the period of ICIs maintenance was not significant compared to that maintained ICIs without TRT in ES-SCLC, suggesting that the administration of TRT as consolidative therapy needs to be further investigated in certain subgroups. TRT benefits survival from a phase III randomized study in the era of two-dimensional radiotherapy ignited the study of TRT in ES-SCLC; however, TRT-mediated local control did not show an advantage[18]. CREST study indicated hypofractionated TRT in ES-SCLC patients responded first-line chemotherapy can benefit 2-year OS (13% vs. 3%, p = 0.004) and local control (19.8% vs. 46.0%) compared to that without TRT[13]. Based on the potent efficacy of TRT for ES-SCLC in the chemotherapy era, it seems to be more pivotal to investigate the role of TRT in ES-SCLC in the immunotherapy era. However, no survival benefits derived from TRT were observed but TRT-mediated LRFS was significantly prolonged in our study. That may be due to the survival benefit from TRT being weakened by the long ICI-induced survival; in addition, the second-line regents may contribute to the prolonged survival. Third, more proportion of distant progression may attenuate the benefits of TRT derived.
However, the subgroup that can benefit from TRT were still hard to identify yet. Specific metastatic organ or metastatic load seems to have an impact on survival. Fewer metastases or oligometastasis seem to contribute to better survival but with liver metastases were not[19, 20]. Advantage of maintained immunotherapy on survival does not seem to be true for cases with liver metastases. Liver metastases (OR 5.69, p = 0.069) were a trend with prognostic factors associated with reaching the maintenance phase in IMpower133 exploratory analysis[21]. In our study, liver metastases also decreased survival regardless of TRT delivered or not compared to those without liver metastases (mOS: 15.0 vs. 24.4 months, p = 0.004) and was a negatively independent factor on OS (OR 2.58, p = 0.01).
We noticed that patients with brain metastases have a trend to benefit from TRT. Unlike liver metastases without local-RT, all patients with brain metastases were treated with cranial radiation concomitantly with immunotherapy in 94.1% (32/34) of patients. The trend of better outcomes in BM with TRT may be attributed to the treatment of local lesions; moreover, broken blood-brain barrier due to brain radiation further promotes the permeability of immune agents. Previous studies demonstrated that radioimmunotherapy-induced abscopal effect was rare[22], while multi-site radiation with high- and low-dose for selected lesions might be a curative strategy for systemic disease control[23]. In particular, the tumor immunogenicity (hot or cold), metastatic sites and numbers should be considered cautiously in the context of numerous unsolved mysteries of radioimmunotherapy; moreover, one-size regimen could not solve personalized problems[24]. Radiation as an immunomodulatory drug reverses tumor immune desertification relying upon mobilizing both adaptive and innate immunity[25]. Therefore, only TRT may be insufficient for systemic disease control, particularly in ES-SCLC. Liver radiation plus immunotherapy promoted systemic antitumor immunity, and was relevant to prolonged survival in practice [23,26−28]. Therefore, local treatment of extrathoracic residuals integrated with TRT may be a potentially crucial approach to improve the survival of ES-SCLC.
Several factors affect the survival of TRT to ES-SCLC, not just those mentioned above. The patterns of radiation, such as radiation dose, hyper- or hypo-fractionation, RT frequency, may affect local control and survival[29–31]. In addition, the time to TRT given was more confusing, while TRT administration after 4–6 cycles of chemotherapy like this study or until thoracic disease progressed or other times were still unclear. Furthermore, second-line treatment is very important in ES-SCLC, but lacks the optimal agents after first-line therapy failed. In the present study, second-line chemotherapy significantly prolonged OS compared to chemo-free strategy in 61 patients with disease progression (mOS: 24.5 vs. 21.4 months, p = 0.026). However, second-line therapy based on immunotherapy or antiangiogenesis did not make a significance on survival. It should be noted that this conclusion cannot be generalized to a larger population because of the results concluded from a subset of a small sample.
Based on concerns about the increased toxicity of radiotherapy combined with ICIs, ICIs were commonly suspended during TRT in clinical practice. However, the toxicity of concurrent TRT and pembrolizumab in limited-stage SCLC was acceptable[32]. Moreover, TRT with pembrolizumab concurrently in ES-SCLC was also well-tolerated, with only 6% of patients experiencing grade 3 adverse events and no grade 4–5 toxicities observed[33]. Another retrospective study also showed that only 15% of patients occurred pneumonitis (3 grade 2 and 3 each) in patients with concurrent atezolizumab and TRT[34]. In our study, of 37 patients received TRT and ICIs simultaneously, only 10.6|% of patients underwent grade 3 RIP, while none experienced more serious adverse events.
This study has its own merits. First, this study thoroughly analyzed the impact of TRT versus non-TRT and second-line treatment on survival in ES-SCLC receiving chemo-immune agents, as well as on local control and toxicity, verified the superiority of TRT on local control and confirmed the feasibility of the combination of radiotherapy and immunotherapy. Second, this study creatively proposed that the management of distant lesions by local therapy might be a potentially curative approach for ES-SCLC. The attitude to metastatic sites should be more aggressive in the subsettings. However, small sample sizes of this retrospective study from a single cancer center increased the inherent flaw of selection bias, which further contribute to the insufficient power of statistical efficacy in certain subgroup analyses. In addition, the correlation of radiation parameters and survival was not performed, such as radiation dose, RT technique, etc. Ultimately, the impact of metastatic load on survival was not further explored, such as numbers of metastatic lesions and/or organs.
In conclusion, the consolidative TRT in the period of ICIs maintenance did not prolong survival, but increased LRFS, and the trend of TRT benefits in subgroups made it more worthy to study in the era of radioimmunotherapy.