The development of immunotherapy has led to a shift in the approach to treating SCLC owing to the development of ICIs that target the PD-1/PD-L1 pathway. For individuals with SCLC, atezolizumab or durvalumab are the primary choice. With the two studies changing the first-line treatment mode of extensive stage small cell lung cancer (ES-SCLC), in the IMPOWER133 and CASPIAN trials, compared with chemotherapy alone, the survival rate (OS and PFS) of patients receiving atezolizumab or durvalumab plus chemotherapy (platinum plus etoposide) in the first-line has been significantly improved [6, 7]. However, there is no new drug approved for LS-SCLC, including immunotherapy. Whereas the clinical study of James W[8] shows that the phase 1/2 trial of Pembrolizumab and concurrent chemoradiotherapy in the treatment of LS-SCLC have good safety and efficacy. The results of a study led by Bilani et al, who disposal a big national database, indicate that immunotherapy did not in dramatically increase survival as first-line treatment for LS-SCLC patients[9]. The efficacy and safety of immunotherapy in limited-stage small cell lung cancer are still inconclusive. At the same time, SCLC is closely related to smoking and is a neuroendocrine carcinoma with high tumor mutation burden, which indicates that patients may benefit from immunotherapy.
In the present study, patients with LS-SCLC were administered with the anti PD-L1 plus CRT as the initial therapy and then compared with CRT. The immune response is mediated by T lymphocytes, which is an important indicator for clinical assessment of the body's immune function[10]. CD3+ enhance the body's anti-tumor immune response, CD4+ play more of an immunomodulatory and paracrine role, and CD8+, CD4+/CD8+ mainly reflect the killing activity of tumor cells[11] .Accordingly, the monitoring of lymphocyte subsets has guiding significance for evaluating tumor drug efficacy. When malignant tumors occur in vivo, the counts of CD3+, CD4+ and CD8+ due to the secretion of certain factors, lead to a disturbed immune response, PD-L1 can enhance the anti-tumor effect of the body and improve the prognosis of patients by reducing the immunosuppressive effect of the body. The results of this study found that after treatment, CD3+ and CD4+, CD4+/CD8+ levels in the study group were significantly higher than those in the control group before treatment. High expression of CD3+ has been shown to be associated with good prognosis in SCLC[12, 13]. Rathore AS[14] showed that higher expression levels of CD3+, CD4+, CD8+ and FOXP3 were associated with better survival. It has been shown that reduced CD8+ T lymphocytes are associated with better prognosis, contrary to the data herein on CD8+ expansion, which may be related to the clinical efficacy of anti-PD-L1 inhibitors[15], which can interfere with PD-L1 signaling and thus promote early CD8+ proliferation[16] without affecting PD-L1 efficacy[17]. All these results suggest that PD-LI mobilizes the patient's own antitumor capacity, probably because PD-L1 inhibitors enhance the body's antitumor capacity by activating T lymphocytes with a killing effect after relieving the inhibitory effect of immune checkpoints.
Tumor markers are produced and secreted by human tumor tissues and cells[18], and their levels are positively correlated with the severity of the patient's condition[19] NSE is a sensitive marker of neuroendocrine tumors, which can reflect the occurrence and progress of tumors; Pro GRP is an important marker for tumor condition and prognosis evaluation. Its expression level is positively correlated with the severity of the disease, which is of great significance for disease condition evaluation and prognosis prediction[20–22]. CYFRA21-1 can be released into the blood when tumor cells are lysed or necrotic, which has a high diagnostic and efficacy assessment in SCLC patients[23].There was no significant difference between the two groups of patients before and after CEA treatment, which may be related to the fact that CEA positive rates are more frequently expressed in lung adenocarcinoma[24] .There was no significant difference in baseline markers between the two groups in this research. After treatment, the levels of serum NSE and Pro GRP in the observation group were lower than those in the control group, indicating that the treatment scheme could reduce the level of serum tumor markers. PD-L1 can activate the immune system, attack cancer cells, form the basis of tumor immunotherapy, effectively alleviate the patient's condition, and reduce the expression of serum factors.
The data of this study also showed that the incidence of thrombocytopenia, nausea and vomiting, leukopenia, neutropenia, anemia, and pneumonia in the study group were 10.0%, 40.0%, 45.0%, 50.0%, 25.0%, and 25.0%, respectively, compared with 13.6%, 40.9%, 50.0%, 45.5%,27.3%, and 9.1% of the control group, there was no statistically significant difference (p > 0.05), indicating that adjuvant immunotherapy did not significantly increase adverse reactions and had good safety. The results showed that anti-PD-L1 plus CRT had appropriate safety at least in the short term. Due to the short follow-up period of this study (median 15.3 months), long-term toxic reactions (e.g pericarditis and esophageal fistula) were not evaluated at the time of this analysis. Also, this paper did not count eosinophils, which are extremely important cells in immune and allergic reactions, releasing granule contents, causing tissue damage and promoting the progression of inflammation. We are cautiously optimistic about the risk of long-term complications. In terms of toxicity and side effects, the incidence of toxicity between the two groups was similar, and there was no new safety signal. In terms of immune adverse reactions such as hypothyroidism and rash, the symptoms were controllable after symptomatic treatment However, foreign studies have also shown that the use of anti-PD-L1 immunotherapy may increase the risk of liver and kidney function and thyroid function damage in patients[25]. Therefore, attention should be paid to regular monitoring of patients' biochemical indicators during use Patients take 10 mg/kg Durvalumab every 3 weeks instead of ES-SCLC (1500 mg every 4 weeks). Immunotherapy has a wide therapeutic index and unique pharmacokinetic and pharmacodynamic behavior. We predict that this adjustment will not affect the efficacy[26]
Results showed that compared with CRT, the anti PD-L1 plus CRT significantly improved the ORR, DCR, PFS, and depth of tumor remission. PFS in the study group was significantly longer than that in the control group (p < 0.05). The mechanism of the synergistic effect of CRT and tumor immunotherapy may explain this[27]. As an important part of cancer treatment, CRT can improve the effectiveness of immunotherapy by increasing antigen presentation, increasing T cell recruitment, increasing tumor interstitial lymphocyte infiltration and changing the microenvironment. In the randomized phase III CONVERT trial, it was shown that 30 times of chest radiation combined with synchronous chemotherapy twice a day of 45 Gy was still the standard treatment, while 33 times of daily fractionated radiotherapy and chemotherapy were 66 Gy, which had similar therapeutic effects and tolerable toxicity characteristics[28]. The characteristics and genetic background of Chinese patients may be different from those of Western patients. The ORR and DCR of the study group tended to increase, but there was no significant difference between the two groups (p > 0.05). This may be due to the limited number of patients, The tumor burden of the study group is usually reduced within a few months. The depth of tumor remission in the study group was better than that in the control group.
This study has the following shortcomings: This is a retrospective study, the expression of anti-PD-L1 was not detected; Due to the small sample size and relatively short follow-up time, the ability of anti-PD-LI and combination of chemoradiotherapy is limited. There are differences in individual chemoradiotherapy doses, and there may be deviations in efficacy and side effects. Therefore, the sample size needs to be expanded for further research.
To sum up, the T lymphocyte subsets (CD3+, CD4+, CD4+/CD8+), tumor markers (Pro-GRP, NSE) and curative effect in patients with LS-SCLC after treatment with anti-PD-L1 immunotherapy were significantly improved compared with those before treatment, and the improvement was better than that of CRT Therefore, anti-PD-L1 immunotherapy plus CRT as the initial treatment choice for LS-SCLC patients, because it has good safety and efficacy, which is an important step to provide a feasible treatment plan for LS-SCLC patients.