Our study indicated that the potential synergistic effect of radiotherapy and immunotherapy in SCLC is promising but still required further exploration. Mainly, this retrospective analysis showed that TCRT after the first-line immuno-chemotherapy could further improve survival and extracranial control of stage IIIA-IVB unresectable SCLC patients.
Though concerns on immuno-chemotherapy combined with radiotherapy in SCLC are increasing, few results has been reported. Of two recently published phase 2 studies both focusing on LS-SCLC, one showed that patients received durvalumab and EP plus thoracic radiotherapy exhibited promising clinical efficacy(mPFS 14.4m, 2y-PFS 42%; mOS NR,2y-OS 67.8%) [16], the other was the study with SHR1316 reported in ASCO2022 as outlined previously(mPFS 7.56m). Both Durvalumab and SHR 1316 are anti-PD-L1 antibodies. In our TCRT evaluation cohort of 27 patients, 20 patients(74.07%) underwent Atezolizumab, Durvalumab or SHR1316. 12 patients(80.00%) who received the TCRT were alive at their last follow-up(mPFS 8.6m, 2y-PFS 32.00%). This were consistent with the results of the above two researches though more extensive stage patients were included. And the 2y-OS rate, 72.22%, was even slightly superior to them due to our shorter follow-up time. Overall, the clinical outcome of addition of TCRT substantially outperformed the CREST trial(TRT group, mPFS 4m, 2y-OS 13%), which reflected a synergistic effect of RT and ICIs.
Impressively, of 7 patients treated with the PD-1 inhibitors, only one of three patients in the TCRT group died at the end of follow-up while 4 patients all died in the non-TCRT group. Though highly mutated, SCLC is poorly immunogenic with downregulation of MHC class I, low expression of PD-L1, lower effector T cells infiltration and presence of regulatory T lymphocytes [17–20]. Inducing T cells exhaustion may lead to most anti-PD-1 antibodies failure in ES-SCLC. Radiotherapy can modify the tumor microenvironment by activating regulatory pathways such as DAMPs, NKG2D, and MHC1 pathways, to enhance the anti-tumor immune responses [21–24]. Thus, addition of radiotherapy is expected to have more efficacy than anti-PD-1 monotherapy. And recently, Serplulimab as an anti-PD-1 inhibitor made the first breakthrough for SCLC in the ASTRUM-005 study [11], the combination of radiotherapy with different ICIs such as Serplulimab will incur further investigation.
Moreover, current researches illustrated that local irradiation caused the tumors away from irradiated field to regress, the so-called abscopal effect, which mediated by immune mechanisms. Our study found that immunotherapy combined with TCRT could improve DPFS, suggesting the systemic immune response was activated by the addition of radiotherapy. However, further data is warranted
In the CREST study which enrolled ES-SCLC patients only [12], radiotherapy was administered with 30Gy in 10 fractions. 2y-OS rate was prolonged from 3–13% (p = 0.004), and mPFS were 4m vs. 3m for TRT and non-TRT groups(p = 0.001), respectively. In our dose subgroup analysis, 45Gy in 15 fractions may further improve the survival(2y-OS of 75.76%) and local control rate though the stage may be a confounding factor, suggesting the prospect of dose escalation strategy for ES-SCLC. However, our small number study needs further prospective larger clinical trials to validate our findings.
Our study revealed that SRT after immuno-chemotherapy was dissatisfactory. In a post hoc analysis of the PACIFIC study, patients underwent Durvalumab within 14 days of chemoradiotherapy ending could significantly gain more PFS benefit than those after 14 days (HR 0.39, 95%CI 0.26–0.58) [25]. In SCLC, based on the synergism of radiotherapy and immunotherapy, radiotherapy was expected to join in earlier when it was in low diffusivity, though insufficient expert consensus due to increased toxicities and lack of evidence. Moreover, given the experience of NSCLC, there is accumulating evidence on early irradiation.
The role of PCI in ES-SCLC has been controversial, especially in immunotherapy era. Although supported by the CREST study and a phase 3 randomized trial from Toshiaki Takahashi et al. [26], PCI was only permitted in the platinum–etoposide group at the investigator’s discretion in the CASPIAN study. Immunotherapy showed benefit for brain metastases compared to chemotherapy only (median OS of 12.00m vs 8.80m, HR = 0.69). Nevertheless, there was still no unified conclusion if immunotherapy could exempt the use of PCI. In our SCLC patients underwent combined immunotherapy, adding PCI could reduce the risk of brain metastases and show a prolonged OS trend though the cases number was small. And no adverse events of grade 3 or higher occurred regarding the use of PCI concurrently with ICIs. Thus, PCI might still play an important role in the immunotherapy era. This hypothesis is supported by a phase II study of applying durvalumab with chemoradiotherapy in LS-SCLC, in which brain metastases events of those underwent PCI (43 patients) were significantly less than those not(13.6% vs 42.9%, p = 0.033) [16]. Moreover, although our subgroup analysis also suggested that TCRT may reduce the risk of mortality, regardless of brain metastases or not, intracranial failure remained the most frequent failure pattern. Once it occurred, the prognosis was extremely poor even if salvage BRT was delivered. The cerebral management of SCLC patients represents a great challenge.
Overlapping toxicities is an increasing concern on combination of radiotherapy and immunotherapy. Among several studies discussed in this manuscript, the serious adverse events were modest and acceptable. In NSCLC, the PACIFIC study showed a similar grade 3 or higher lung toxicity between two groups (3.4% vs 2.6%, p > 0.50) [13]. In SCLC, a phase 1/2 trial of Pembrolizumab and concurrent chemoradiation therapy for limited-stage patients showed well tolerance: there were no grade 5 toxicities, and grade 3 to 4 pneumonitis rate was 15% [27]. In our study, overall, ICIs combined with radiotherapy were well tolerated, with severe AEs and irAEs of 33.33% and 19.61%, separately. A sixty-four years old male patient in stage IIIB underwent TCRT with 30Gy/10f, suffered from grade 5 pneumonitis. The primary tumor site was the middle lobe of the right lung with right hilum and mediastinal lymph nodes metastases, and the maximum diameter was 5.4cm. The actual dose of organs at risk(OARs) was as follows: V20 = 14.67% and Dmean = 7.69Gy for entire lung, V20 = 20.56% and Dmean = 9.60Gy for the right lung, V20 = 7.51% and Dmean = 5.37Gy for the left lung. He received one cycle Durvalumab during TCRT, then developed fever, dyspnea and interstitial changes in both lungs. Immune-related pneumonia was diagnosed by clinical symptoms and imaging findings. And this patient was diagnosed of bullous emphysema with an over 30 years history of smoking, which may increase the risk for severe pneumonia.
Naturally, this study is a retrospective study with an inevitable selection bias, as well as a limited sample size. But our study highlights the important role of radiotherapy in SCLC and potential applicability of this treatment modality, the combination of immuno-chemotherapy and consecutive TCRT. We provides the preliminary efficacy and safety data for future exploration and clinical application. One pertinent phase 2 clinical trial(NCT02701400) is currently under investigation, which is focus on the efficacy and safety of ICIs plus radiotherapy for recurrent SCLC patients [28]. To know whether immunotherapy combined with radiotherapy could enhance the abscopal effect and further reduce the risk of distant metastasis [29], randomized controlled trials with larger sample size are required. Considering various doses, fractionations, modalities and radiotherapy technology could influence the clinical outcome potentially, the integrated management of SCLC patients still has a long way to go.