thoracic consolidation radiotherapy for es-sclc treated with chemo-immunotherapy

Conditions: Small Cell Lung Cancer Extensive Stage

Summary: this study intends to recruit es-sclc patients with response to standard first-line chemo-immunotherapy to assess the safety of receiving different doses of consolidative thoracic radiotherapy.

approximately two-thirds of small-cell lung cancer (sclc) patients are in the extensive stage (extensive-stage sclc, es-sclc) at the time of diagnosis, and the 5-year survival rate of these patients is less than 5%. before the immunotherapy era, the standard first-line treatment for es-sclc had been platinum-based chemotherapy regimens combined with etoposide. since treatment failure patterns revealed high probability of residual thoracic disease and high risk of progression of thoracic lesions after es-sclc chemotherapy, previous studies suggest that thoracic consolidation radiotherapy in es-sclc patients who are sensitive to first-line chemotherapy can reduce the risk of thoracic recurrence and improve overall survival time. slotman et al. further conducted a phase iii randomized controlled clinical study to explore the application of thoracic consolidation radiotherapy in es-sclc (crest study). the crest study results showed that in es-sclc patients who responded to chemotherapy and had residual thoracic lesions, thoracic residual lesion radiotherapy (30 gy/1 0fx) combined with prophylactic brain radiotherapy could reduce the risk of thoracic recurrence by 50% and increase the 2-year survival rate from 3% to 13%. with the advent of the era of immunotherapy, the impower133 trial showed that the combination of atezolizumab and chemotherapy prolonged the median overall survival time of es-sclc patients compared with the chemotherapy alone group. in the caspian study, the combination of dulvumab and chemotherapy also resulted in a survival benefit. the astrum-005 study using pd-1 monoclonal antibody serplulimab in combination with chemotherapy also achieved prolonged overall survival. although the overall median survival of es-sclc is prolonged after immunotherapy in combination with chemotherapy, patients who truly achieve long-term survival are still limited, with a 3-year os rate of about 15% - 20%. accordingly, it is necessary to explore effective methods to combine radiotherapy and maximize the benefit population of immunotherapy in es-sclc. failure pattern analysis revealed that, consistent with the era of non-immunotherapy, the main progression phenotype in patients receiving first-line chemotherapy + immunotherapy remained thoracic progression, suggesting that sequential thoracic consolidation radiotherapy is still likely to achieve clinical benefit in es-sclc patients receiving chemo-immunotherapy. immunotherapy combined with concurrent chemoradiotherapy has shown good safety and survival benefit in limited-stage sclc. in non-small cell lung cancer (nsclc), the safety of sequential immunotherapy after thoracic chemoradiotherapy has also been verified. however, there is a lack of prospective studies to investigate the safety of sequential thoracic consolidation radiotherapy after first-line immunochemotherapy in es-sclc patients. at present, the widely used es-sclc thoracic consolidation radiotherapy regimen is based on the 30 gy/1 0fx dose fractionation of crest study. at the same time, it has been shown that increasing the dose of single radiotherapy within a certain range helps to increase the production of immunogenic death by tumor cells, that is, more tumor-specific antigens that can be recognized by the immune system are produced during the induction of tumor cell death. therefore, this study intends to perform a dose escalation study based on 30 gy/10fx dose fractionation and assess the safety of this treatment mode.

Eligibility criteria:
inclusion criteria: inclusion criteria: 1. age ≥ 18 years; 2. ecog performance status score 0-2 points; 3. pathologically confirmed small cell lung cancer; 4. complete baseline imaging data (including brain enhanced mri/ct, pet-ct or chest enhanced ct + bone scan + neck and abdominal b ultrasound/ct) before first-line treatment; 5. stage extensive-stage sclc at initial diagnosis, and first-line treatment received standard platinum-based doublet chemotherapy combined with immunotherapy (pd-1 or pd-l1) for at least 4 cycles after the efficacy assessment of sd or pr (residual lesions assessed by chest ct); 6. no history of other malignancies; 7. reproductive age male/female agreed to contraception during the trial (surgical ligation or oral contraceptives/intrauterine devices + condom contraception); 8. life expectancy ≥ 3 months 9. 1 week before enrollment, the investigator judged that the patient could continue immune maintenance therapy at the same time, and the organ function level meets the following criteria: 1) bone marrow function: hemoglobin ≥ 80 g/l, white blood cell count ≥ 4.0 \* 10 \^ 9/l or neutrophil count ≥ 1.5 \* 10 \^ 9/l, platelet count ≥ 100 \* 10 \^ 9/l; 2) liver: serum total bilirubin level ≤ 1.5 times the upper limit of normal, when serum total bilirubin level \> 1.5 times the upper limit of normal direct bilirubin level must be ≤ the upper limit of normal,aspartate aminotransferase (ast) and alanine aminotransferase (alt) ≤ 2.5 times of the upper limit of normal; serum albumin ≥ 27 g/l; 3) kidney: serum creatinine level \< 1.5 times of the upper limit of normal or creatinine clearance ≥ 50 ml/min, urea nitrogen ≤ 200 mg/l; 10.patients must have the ability to understand and voluntarily sign an informed consent form. exclusion criteria: 1. baseline pathological examination found mixed with non-small cell lung cancer components; 2. patients who had used any anti-tumor therapy before the diagnosis of es-sclc; 3. patients who had received anti-tumor therapy other than standard chemotherapy + immunotherapy regimen; 4. patients who had pd assessed by chemotherapy combined with immunotherapy efficacy; 5. patients who had no residual thoracic lesions (lung, mediastinal and supraclavicular metastatic lymph nodes, thoracic efficacy cr) on chest enhanced ct during efficacy assessment; 6. patients with severe immune-related toxicities after treatment; 7. symptomatic interstitial lung disease or active infection/non-infectious pneumonia; 8. patients who required long-term use of cortisol or immunosuppressive agents; 9. allergic to pd-1 or pd-l1 monoclonal antibody immunotherapy or other causes of inability to perform immune maintenance therapy; 10. lactating or pregnant women; 11. patients with severe autoimmune diseases: active inflammatory bowel disease (including crohn 's disease, ulcerative colitis), rheumatoid arthritis, scleroderma, systemic lupus erythematosus, autoimmune vasculitis (such as wegener' s granulomatosis), etc.; 12. researchers believe that physical examination or clinical trials may interfere with the results or increase the risk of treatment complications, or other uncontrollable diseases; 13. patients with mental illness, substance abuse, social problems affecting compliance are not enrolled after the doctor 's review.

Keywords: small cell lung cancer chemotherapy immunotherapy thoracic radiotherapy