Abstract
Background
To date, there remains a paucity of comparative investigations pertaining to preoperative immunochemotherapy and conventional chemotherapy in the context of limited-stage small-cell lung cancer (LS-SCLC) patients. This study conducted a comprehensive comparative assessment concerning the safety and efficacy profiles of preoperative immunochemotherapy and chemotherapy in individuals diagnosed with stage I–IIIB SCLC.
Methods
This investigation collected 53 consecutive patients diagnosed with LS-SCLC spanning stage I to IIIB who underwent preoperative immunochemotherapy or conventional chemotherapy at our hospital from January 2019 to July 2021. Patients were allocated to receive 2–4 cycles of neoadjuvant immunochemotherapy or chemotherapy, with each cycle lasting three weeks. Comprehensive analyses encompassed baseline characteristics, clinical staging, tumor response, intraoperative and postoperative outcomes, and the assessment of treatment-related adverse events (trAEs). The follow-up period is extended for a minimum of one year after surgery. The primary endpoint embraced the evaluation of the pathological response [major pathological response (MPR) and pathological complete remission (pCR)], while secondary endpoints encompassed objective response rate (ORR), trAEs, surgical resection rates, and disease-free survival (DFS).
Results
The objective response rate of the immunochemotherapy group was 89.5%, while that of the chemotherapy group was 75.0% (P = 0.206). A total of 19 patients underwent surgery among these 53 patients, with 14 patients in the neoadjuvant chemoimmunotherapy group and 5 patients in the chemotherapy group. And the surgical resection rate of the immunochemotherapy group was 48.3% (14/29), which was higher than the chemotherapy group (20.8%, 5/24, P = 0.038). The rate of MPR in the immunochemotherapy group was 57.1% (8/14) and 40.0% (2/5) in the chemotherapy group (P = 0.891). The rates of pCR in the immunochemotherapy and chemotherapy group were 50.0% (7/14) and 0.0% (0/5), respectively (P = 0.106).The median DFS for both groups were not reached (P = 0.43). The 2-year DFS rate was 21.4% for the immunochemotherapy group versus 40.0% for the chemotherapy group. There was no significant difference in the incidence of grade 3–4 adverse events between the immunochemotherapy group and the chemotherapy group.
Conclusions
For patients with stage I–IIIB SCLC, neoadjuvant immunochemotherapy is feasible and safe. Although immunochemotherapy did not significantly associated with longer DFS versus chemotherapy alone in patients with stage I–IIIB SCLC, it can produce significant downstaging and increase the possibility of surgery.
Keywords: Immunochemotherapy, Chemotherapy, Neoadjuvant treatment, Small-cell lung cancer, Surgery
Introduction
Small-cell lung cancer (SCLC) is considered an extremely aggressive neuroendocrine lung carcinoma and is characterized by high proliferative activity and a tendency of early metastasis [1, 2]. It remains a disease of poor prognosis and the 5-year survival rate is less than 7% [3, 4]. SCLC accounts for approximately 13–15% of all lung cancer [5] and about one-third of patients present with limited-stage (LS) disease [6], which is defined as no distant metastasis according to the International Association for the Study of Lung Cancer staging criteria and corresponds to stages I–IIIB of the TNM staging system [7].
Nowadays, concurrent chemotherapy plus radiotherapy is the standard management for limited-stage SCLC (LS-SCLC) [8]. Two meta-analyses revealed that adding thoracic radiotherapy to chemotherapy could result in survival benefits and improve local tumor control of patients with LS-SCLC [9, 10]. Then, three randomized trials demonstrated that early concurrent chemotherapy plus radiotherapy could produce better effects than sequential chemotherapy plus radiotherapy [11–13]. Moreover, the Intergroup 0096 study showed that 45 Gy twice-daily thoracic radiotherapy could yield improved survival and reduced risk of thoracic relapse compared with 45 Gy once-daily thoracic radiotherapy [14]. And a recent phase 2 trial found that high-dose twice-daily thoracic radiotherapy (60 Gy) resulted in significant survival improvement compared with standard-dose twice-daily thoracic radiotherapy (45 Gy) [15]. Although LS-SCLC is extremely responsive to chemoradiotherapy, it almost invariably relapses and has unsatisfactory results. The 2-year survival rate is less than 50%, and the median survival period is 16–24 months [16, 17].
So far, immunotherapy plus chemotherapy has played significant roles in the management of extensive-stage SCLC (ES-SCLC). Some related researches indicated that SCLC might be immunogenic due of its high frequency of mutation and response to immune checkpoint inhibitors [18, 19]. Recent studies have shown that immunochemotherapy for patients with ES-SCLC may be more effective than chemotherapy [20–24]. However, there are still few comparisons between neoadjuvant immunochemotherapy and chemotherapy for patients with LS-SCLC. The ADRIATIC study [25] is a Phase III, randomized, double-blind, placebo-controlled clinical trial investigating the efficacy and safety of durvalumab, a PD-L1 inhibitor, with or without tremelimumab, a CTLA-4 inhibitor, as consolidation therapy in patients with LS-SCLC who achieved disease stability after concurrent chemoradiotherapy. The findings in the study establish durvalumab as the first immune checkpoint inhibitor to achieve statistically significant OS benefit in a Phase III clinical trial for LS-SCLC, marking a paradigm shift in the treatment landscape for this aggressive malignancy and providing high-quality evidence-based medicine for clinical practice in LS-SCLC. Currently, the most effective treatment for lung cancer is surgery (as part of the multimodality therapy). Although surgical resection was now recommended only for c-stage I–IIA (T1–2N0M0) SCLC in the NCCN Clinical Practice Guidelines, surgery could also improve survival outcomes in patients with II-III LS-SCLC [26–28]. Therefore, we launch this study to compare the safety and efficacy of neoadjuvant immunochemotherapy and chemotherapy for patients with potentially resectable stage I–IIIB SCLC.
Methods
Study design and patients
This retrospective study was carried out at the Department of Thoracic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine from 2019 to 2021. Key eligibility criteria for patients were as follows: (I) age over 18 and under 80 years; (II) histopathologically diagnosed SCLC by bronchoscopy or lung aspiration; (III) pretreatment clinical stage I–IIIB SCLC; (IV) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. We excluded patients with the following situations: (I) absence of pretreatment imaging evaluations in our hospital; (II) absence of imaging examinations more than 2 times; (III) receipt of previous anticancer treatment, such as radiotherapy, interventional therapy or drug treatment; (IV) coexisting autoimmune disease or infectious disease; (V) coexisting ongoing systemic immunosuppressive treatment; (VI) coexisting other malignant tumors; and (VII) occurrence of distant metastases.
This study was approved by the Clinical Research Ethics Committee of the First Affiliated Hospital, Zhejiang University School of Medicine (2022 IIT No. 1166), and done in accordance with the Declaration of Helsinki (as revised in 2013) and Good Clinical Practice Guidelines. Written informed consent was obtained from patients so that we could acquire and use required information from their medical record in our hospital.
Treatment procedures
Enrolled patients were assigned to receive 2–4 cycles (3 weeks per cycle) of neoadjuvant immunochemotherapy or chemotherapy. Immunotherapy regimen included camrelizumab 200 mg, durvalumab 1000 mg, nivolumab 200 mg, sintilimab 200 mg, tislelizumab 200 mg or pembrolizumab 200 mg. Chemotherapy regimen comprised etoposide 100 mg/m2, cisplatin 75 mg/m2 or carboplatin area under the curve (AUC) under the drug plasma concentration = 5. Detailed information was revealed in Fig. 1. After 2 cycles of immunochemotherapy or chemotherapy, patients would be evaluated to determine whether there was an opportunity for surgery by a multidisciplinary team (including surgeons, anesthesiologist, radiologist, oncologist, etc.). If the patient was not tolerated to neoadjuvant therapy, it would be made appropriate changes to the treatment plan or be postponed according to the NCCN Clinical Practice Guidelines in Oncology [John A, Bryan J, Julie B, et al. NCCN Clinical Practice Guidelines in Oncology. Management of immunotherapy related toxicity. Version 2. 2019.]. If the tumor had no obvious regression, therapy would continue and evaluation on surgical possibility would be performed after 1–2 cycles. If there was disease progression, radiotherapy would be recommended.
Fig. 1.
The design flowchart of this study
Surgical approaches are comprised of open radical surgery or video-assisted thoracoscopic surgery (VATS) with routine lymph node dissection. The lymph node dissection scope in our study includes at least 3 groups of lymph nodes in the lung and 3 groups of mediastinal lymph nodes, which must include subcarinal lymph nodes. Group 3, 4 L, 5–13 lymph nodes on the left side and group 3a, 4R, 7–13 lymph nodes on the right side are generally dissected. The follow-up date lasted at least 1 years after surgery, giving up treatment with the patient’s decision, or termination of the study. We obtained follow-up data from patients through their regular examinations or treatment in our hospital. If we can’t complete it, contacting patients by telephone or WeChat would be adopted by us.
End points and assessments
The primary endpoint of this study was pathological response, and the secondary endpoints were objective response rate (ORR), adverse reactions, surgical resection rate, and disease-free survival (DFS).
Before and after neoadjuvant therapy, systematic imaging evaluations were performed in these patients, including computed tomography (CT) of the chest and abdomen, endoscopic ultrasound, positron emission tomography (PET)–CT, bone emission computed tomography, brain magnetic resonance imaging and ultrasound, to assess the tumor status and to obtain baseline data. During the neoadjuvant therapy period, chest CT was conducted every 2 cycles until surgery or patient’s withdrawal from the treatment (This surveillance period was preplanned according to clinical practice at our center). Routine blood and biochemical blood examinations were done every week, and myocardial enzyme spectrum, thyroid function and coagulation function examinations were conducted every 3 weeks. Gastrointestinal reactions and skin reactions were evaluated by patients’ complaints. After surgery, imaging assessments were performed every 1–3 months. And adjuvant treatment (like immunochemotherapy, immunotherapy, chemotherapy or radiotherapy) would be considered. We collected data including baseline characteristics, clinical stage and tumor response, intraoperative and postoperative outcomes, and treatment-related adverse events (trAEs) etc.
The eighth edition of the AJCC TNM staging was adopted to determine the cTNM, ycTNM and ypTNM [29]. The tumor treatment response was evaluated according to the Response Evaluation Criteria in Solid Tumor version 1.1 (RECIST 1.1) [30] -- complete response (CR): vanishment of all target lesions, partial remission (PR): at least 30% decline in the total diameter of target lesions, progressive disease (PD): at least 20% enlargement in the total diameter of target lesions or the emergence of new lesions, stable disease (SD): neither CR, PR nor PD. ORR included CR and PR. DFS was defined as the time from surgical resection to disease progression according to RECIST 1.1 or death, whichever occurred first. We used tumor regression grade (TRG) to express pathological response, which was divided into four categories on the basis of the College of American Pathologists (CAP)/The National Comprehensive Cancer Network (NCCN) guidelines: TRG 0 (no viable tumor cells), TRG 1 (viable tumor cells ≤ 10%), TRG 2 (10%< viable tumor cells ≤ 50%) and TRG 3 (viable tumor cells > 50%). The pathological complete remission (pCR) rate and major pathological response (MPR) rate were considered as equivalent to TRG 0 and TRG 0–1 respectively. AEs were graded according to Common Terminology Criteria for Adverse Events [CTCAE] version 5.0 [U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 5. Published: November 27, 2017.].
Statistical analysis
Categorical variables were expressed as frequencies(percentages), and the chi-square tests and paired Wilcoxon test were used to compare differences between groups. After Normality Test, continuous variables were shown as the median and interquartile range (IQR), and differences between groups were compared with the t-test or Wilcoxon test. Kaplan-Meier method was used to evaluate DFS and differences between groups were compared with the stratified log-rank test. All analyses were performed with R software (version 4.1.2). A two-sided P value of less than 0.05 was considered to be significant.
Results
Characteristics at baseline
From 2019 to 2021, a total of 53 patients were included in our study: 29 patients received immunochemotherapy, and 24 patients received chemotherapy (Fig. 2). Characteristics of these patients at baseline are shown in Table 1. No significance was observed between the two groups in age, gender, ECOG performance status, smoking status, drinking status, comorbidities, clinical stage and treatment cycles.
Fig. 2.
The flowchart of case screening
Table 1.
Characteristics of the patients at baseline, according to neoadjuvant regimen (n = 53)
| Characteristic | Total, n = 53 | Chemotherapy, n = 24 | Immunochemotherapy, n = 29 | P-value |
|---|---|---|---|---|
| Median age (IQR), years | 66.0 (59.0–70.0) | 66.0 (58.8–71.3) | 65.0 (60.0–69.0) | 0.870 |
| Sex, n (%) | 0.429 | |||
| Male | 44 (83.0) | 21 (87.5) | 23 (79.3) | |
| Female | 9 (17.0) | 3 (12.5) | 6 (20.7) | |
| ECOG performance status | 0.630 | |||
| 0 | 29 (54.7) | 14 (58.3) | 15 (51.7) | |
| 1 | 24 (45.3) | 10 (41.7) | 14 (48.3) | |
| Smoking status, n (%) | 0.178 | |||
| Never | 11 (20.8) | 3 (12.5) | 8 (27.6) | |
| Ever | 42 (79.2) | 21 (87.5) | 21 (72.4) | |
| Drinking status, n (%) | 0.157 | |||
| Never | 44 (83.2) | 18 (75.0) | 26 (89.7) | |
| Ever | 9 (16.8) | 6 (25.0) | 3 (10.3) | |
| Comorbidities, n (%) | ||||
| Pulmonary disease | 3 (5.6) | 0 (0.0) | 3 (10.3) | 0.305 |
| Cardiac disease | 5 (9.4) | 0 (0.0) | 5 (17.2) | 0.096 |
| Diabetes mellitus | 6 (11.3) | 4 (16.7) | 2 (6.9) | 0.495 |
| Hypertension | 15 (28.3) | 8 (33.3) | 7 (24.1) | 0.459 |
| Clinical stage, n (%) | 0.286 | |||
| IA | 1 (1.9) | 0 (0.0) | 1 (3.4) | |
| IB | 1 (1.9) | 0 (0.0) | 1 (3.4) | |
| IIB | 6 (11.3) | 4 (16.7) | 2 (6.9) | |
| IIIA | 36 (67.9) | 18 (75.0) | 18 (62.1) | |
| IIIB | 9 (17.0) | 2 (8.3) | 7 (24.1) | |
| Treatment cycle, n (%) | 0.346 | |||
| 1 | 1 (1.9) | 1 (4.2) | 0 (0.0) | |
| 2 | 6 (11.3) | 1 (4.2) | 5 (17.2) | |
| 3 | 2 (3.8) | 1 (4.2) | 1 (3.4) | |
| 4 | 44 (83.0) | 21 (87.5) | 23 (79.3) | |
| Therapeutic. evaluation, n (%) | 0.206 | |||
| CR | 2 (3.8) | 0 (0.0) | 2 (6.9) | |
| PR | 42 (79.2) | 18 (75.0) | 24 (82.8) | |
| SD | 7 (13.2) | 4 (16.7) | 3 (10.3) | |
| PD | 2 (3.8) | 2 (8.3) | 0 (0.0) | |
| Immunotherapy regimes, n (%) | NA | |||
| Camrelizumab, 200 mg | 10 (18.9) | 0 (0.0) | 10 (34.5) | |
| Durvalumab, 1000 mg | 6 (11.3) | 0 (0.0) | 6 (20.7) | |
| Nivolumab, 200 mg | 3 (5.7) | 0 (0.0) | 3 (10.3) | |
| Sintilimab, 200 mg | 5 (9.4) | 0 (0.0) | 5 (17.2) | |
| Tislelizumab, 200 mg | 4 (7.5) | 0 (0.0) | 4 (13.8) | |
| Pembrolizumab, 200 mg | 1 (1.9) | 0 (0.0) | 1 (3.4) |
Abbreviations: IQR, interquartile range; ECOG, Eastern Cooperative Oncology Group; CR, complete remission; PR, partial remission; SD, stable disease; PD, progression disease; NA, not acquired
Response to neoadjuvant therapy
The percentage change in the maximum diameter of target lesion in these patients compared with the baseline tumor size was revealed in Fig. 3A. There were no cases of PD in the immunochemotherapy group, but there were 2 patients with PD in the chemotherapy group, 1 with right supraclavicular lymph node metastases and 1 with lumbar metastases. Two patients presented with a CR (basing on radiological evaluation) in the immunochemotherapy group, but no cases of CR in the chemotherapy group. The objective response rate of the immunochemotherapy group was 89.5%, while that of the chemotherapy group was 75.0% (P = 0.206). Significant maximum diameter decrease was observed after preoperative treatment regardless the groups in Fig. 3B and C. We also compared the change of the maximum diameter of target lesion between two groups (Fig. 3D), but we could see no significant difference between them.
Fig. 3.
(A) The percentage change in the maximum diameter of target lesion compared with the baseline tumor size. (B) The change of in the maximum diameter of target lesion before and after neoadjuvant treatment in the immunochemotherapy group. (C) The change of in the maximum diameter of target lesion before and after neoadjuvant treatment in the chemotherapy group. (D) The change of the maximum diameter of target lesion between the immunochemotherapy group and chemotherapy group
The changes of the clinical stage of these patients before (cStage) and after (ycStage) neoadjuvant treatment (chemotherapy or immunochemotherapy) are shown in Table 2. A significant reduction in the number of patients with T4, T3 and T2, and an obvious increase in the number of patients with T1 after treatment were observed, but there were no significant differences (P > 0.05). The number of patients with N2 decreased, and the number of patients with N0 and N1 increased and a significant difference was observed (P < 0.05). The number of patients in stage III decreased, and the number of patients in stage I increased. However, no significant difference was revealed (P > 0.05). In the chemotherapy group, the N2 downstaging rate was 5.26% (1/19), whereas in the immunochemotherapy group, it was significantly higher at 34.78% (8/23), with 6 patients downstaged to N0 and 2 to N1.
Table 2.
Changes of clinical stage of SCLC patients before (cStage) and after (ycStage) neoadjuvant treatment
| Characteristic | Chemotherapy | Immunochemotherapy | ||||
|---|---|---|---|---|---|---|
| cStage, n = 24 |
ycStage, n = 24 |
P-value | cStage, n = 29 |
ycStage, n = 29 |
P-value | |
| T stage, n (%) | 0.150 | 0.366 | ||||
| T0 | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (6.9) | ||
| T1a | 0 (0.0) | 7 (29.2) | 0 (0.0) | 4 (13.8) | ||
| T1b | 2 (8.3) | 6 (25.0) | 3 (10.3) | 13 (44.8) | ||
| T1c | 2 (8.3) | 4 (16.7) | 2 (6.9) | 7 (29.2) | ||
| T2a | 8 (33.3) | 3 (12.5) | 11 (37.9) | 1 (3.4) | ||
| T2b | 9 (37.5) | 2 (8.3) | 4 (13.8) | 2 (6.9) | ||
| T3 | 4 (16.7) | 1 (4.2) | 5 (17.2) | 0 (0.0) | ||
| T4 | 2 (8.3) | 1 (4.2) | 4 (13.8) | 0 (0.0) | ||
| N stage, n (%) | 0.008 | 0.016 | ||||
| N0 | 4 (16.7) | 4 (16.7) | 2 (6.9) | 8 (27.6) | ||
| N1 | 1 (4.2) | 2 (8.3) | 4 (13.8) | 6 (20.7) | ||
| N2 | 19 (79.2) | 17 (70.8) | 23 (79.3) | 15 (51.7) | ||
| N3 | 0 (0.0) | 1 (4.2) | 0 (0.0) | 0 (0.0) | ||
| Stage, n (%) | 0.054 | 0.115 | ||||
| 0 | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (6.9) | ||
| IA | 0 (0.0) | 4 (16.7) | 1 (3.4) | 6 (20.7) | ||
| IB | 0 (0.0) | 0 (0.0) | 1 (3.4) | 0 (0.0) | ||
| IC | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | ||
| IIA | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | ||
| IIB | 4 (16.7) | 2 (8.3) | 2 (6.9) | 6 (20.7) | ||
| IIIA | 18 (75.0) | 14 (58.3) | 18 (62.1) | 15 (51.7) | ||
| IIIB | 2 (8.3) | 3 (12.5) | 7 (24.1) | 0 (0.0) | ||
Abbreviations: SCLC, small cell lung cancer
Adverse event
There were no previously unreported AEs in our study. There were no patients with immune myocarditis and immune pneumonia in our study. Grade 3 and 4 AEs of neoadjuvant therapy were summarized in Table 3. Grade 3–4 AEs were mainly distributed in hematologic abnormalities. The incidence of grade 3 and 4 AEs was higher in the chemotherapy group than the immunochemotherapy group (29.2% vs. 6.9%), but there was no significant difference (P > 0.05). These AEs were quickly resolved after symptomatic treatment.
Table 3.
Grade 3 and 4 AEs of neoadjuvant therapy
| Total, n = 53 | Chemotherapy, n = 24 | Immunochemotherapy, n = 29 | P-value | |
|---|---|---|---|---|
| Hematologic | ||||
| leukopenia | 2 (3.8) | 2 (8.3) | 0 (0.0) | 0.389 |
| Agranulocytosis | 2 (3.8) | 2 (8.3) | 0 (0.0) | 0.389 |
| Anemia | 4 (7.5) | 3 (12.5) | 1 (3.4) | 0.472 |
| Thrombocytopenia | 0 (0.0) | 0 (0.0) | 0 (0.0) | NA |
| Gastrointestinal | ||||
| Constipation | 1 (1.9) | 0 (0.0) | 1 (3.4) | 0.358 |
| Hepatic injury | 0 (0.0) | 0 (0.0) | 0 (0.0) | NA |
| Skin reaction | 0 (0.0) | 0 (0.0) | 0 (0.0) | NA |
Abbreviations: AE, adverse event; NA, not acquired
Surgery and pathological response
Eventually, a total of 19 patients underwent surgery among these 53 patients, with 14 patients in the neoadjuvant chemoimmunotherapy group and 5 patients in the chemotherapy group. And the surgical resection rate of the immunochemotherapy group was 48.3% (14/29), which was higher than the chemotherapy group (20.8%, 5/24, P = 0.038) (Fig. 4A). Outcomes of surgery and the pathological response were summarized in Table 4. Four patients were converted to open surgery in the immunochemotherapy group, but there were no patients in the chemotherapy group. The operation time of the immunochemotherapy group was more than the other group (P > 0.05). The median number of lymph node dissections during surgery was higher in the immunochemotherapy group than the other group, but there was no significant difference (P > 0.05). The median estimated blood loss and length of hospital stay were equal among these two groups. Most patients had achieved R0 resection. There were no perioperative deaths. The rate of MPR in the immunochemotherapy group was 57.1% (8/14) and 40.0% (2/5) in the chemotherapy group (P = 0.891) (Fig. 4B). The rates of pCR in the immunochemotherapy and chemotherapy group were 50.0% (7/14) and 0.0% (0/5), respectively (P = 0.106) (Fig. 4C).
Fig. 4.
The distribution condition of surgery and pathological response: (A) Surgery, (B) MPR, (C) pCR. Pathological response included major pathological response (MPR) and pathological complete remission (pCR). ns represents P value > 0.05
Table 4.
Outcomes of SCLC patients undergoing surgery
| Total, n = 19 | Chemotherapy, n = 5 | Immunochemotherapy, n = 14 | P-value | |
|---|---|---|---|---|
| Time from first treatment to surgery, median (IQR), day | 96.0 (54.0-108.0) | 104.0 (51.0-111.0) | 94.5 (60.5-103.5) | 0.583 |
| Operation method, n (%) | 0.029 | |||
| Open | 2 (10.5) | 2 (40.0) | 0 (0.0) | |
| VATS | 13 (68.4) | 3 (60.0) | 10 (71.4) | |
| Conversion | 4 (21.1) | 0 (0.0) | 4 (28.6) | |
| Operation time, median (IQR), min | 153.0 (117.5-163.5) | 125.0 (107.0-154.0) | 153.5 (121.0-166.2) | 0.459 |
| Estimated blood loss, median (IQR), mL | 50.0 (20.0–50.0) | 50.0 (20.0–50.0) | 50.0 (27.5–50.0) | 0.961 |
| Number of lymph node dissections during surgery, median (IQR), n | 16.0 (11.5–25.0) | 14.0 (12.0–19.0) | 16.0 (11.3–25.8) | 0.746 |
| Surgical margin, n (%) | 0.539 | |||
| R0 resection | 18 (94.7) | 5 (100.0) | 13 (92.9) | |
| R1 resection | 1 (5.3) | 0 (0.0) | 1 (7.1) | |
| Length of hospital stay, median (IQR), day | 14.0 (9.5–17.0) | 14.0 (14.0–15.0) | 14.0 (9.3–17.5) | 0.853 |
| Postoperative complication, n (%) | 0.539 | |||
| Pyothorax | 1 (5.3) | 0 (0.0) | 1 (7.1) | |
| None | 18 (94.7) | 5 (100.0) | 13 (92.9) | |
| ypTNM stage, n (%) | 0.009 | |||
| 0 | 7 (36.8) | 0 (0.0) | 7 (50.0) | |
| IA | 7 (36.8) | 5 (100.0) | 2 (14.3) | |
| IIB | 2 (10.5) | 0 (0.0) | 2 (14.3) | |
| IIIA | 3 (15.8) | 0 (0.0) | 3 (21.4) | |
| Pathological response, n (%) | 0.073 | |||
| No viable tumor cells | 7 (36.8) | 0 (0.0) | 7 (50.0) | |
| 0 < viable tumor cells ≤ 10% | 3 (15.8) | 2 (40.0) | 1 (7.1) | |
| viable tumor cells > 10% | 9 (47.4) | 3 (60.0) | 6 (42.9) |
Abbreviations: SCLC, small cell lung cancer; IQR, interquartile range; VATS, video-assisted thoracoscopic surgery
Disease-free survival
In the immunochemotherapy group, 21.4% (3/19) patients experienced recurrence and metastasis, and 60.0% (3/5) patients experienced recurrence and metastasis in the chemotherapy group. In our study, the median DFS in the chemotherapy group and immunochemotherapy group didn’t arrive. The log-rank test showed that there was no significant difference between the immunochemotherapy group and the chemotherapy group (P = 0.43), as shown in Fig. 5. The 2-year DFS rate was 21.4% for the immunochemotherapy group versus 40.0% for the chemotherapy group.
Fig. 5.
Kaplan Meier curves of DFS in chemotherapy and immunochemotherapy groups
Discussion
In recent years, more and more researches focused on immunochemotherapy for patients with ES-SCLC. IMPOWER-133 study reported that the ORR in the chemotherapy group was 64.4% with immunochemotherapy group 60.2%20. KEYNOTE-604 study found that the ORR in the chemotherapy and immunochemotherapy group was respectively 61.8% and 70.6% [22]. But there are still few comparisons between neoadjuvant immunochemotherapy and chemotherapy for patients with LS-SCLC. Therefore, we launch this study to compare the safety and efficacy of neoadjuvant immunochemotherapy with chemotherapy as first-line treatment for patients with LS-SCLC. Our study found that the ORR of immunochemotherapy regimen was higher than that of the chemotherapy regimen (immunochemotherapy: 89.5%, chemotherapy: 75%), which were similar to the above studies on the trend. In ADRIATIC study [25], the durvalumab arm demonstrated statistically significant and clinically meaningful improvements in both median OS and PFS compared to the placebo arm, with a median OS of 55.9 months and a median PFS of 16.6 months in the durvalumab group. However, our study did not result in an improved survival outcome, and the median DFS did not arrive. The reason for this result may be short postoperative follow-up period and limited sample size.
Although surgical resection was now recommended only for c-stage I–IIA (T1–2N0M0) SCLC in the NCCN Clinical Practice Guidelines, surgery as part of the multimodality therapy of cancer was found to be effective and could improve survival outcomes in patients with II-III LS-SCLC [26–28]. Therefore, we have expanded the indications for surgery in our study and surgery was considered for stage I–IIIB SCLC after neoadjuvant therapy. We assumed that the tumor could shrink, even achieve down-staging after neoadjuvant therapy, and that a more comprehensive removal of the tumor could be achieved with future tumor resection.
In our study, we could see significant downstage whether after undergoing chemotherapy or immunochemotherapy. The surgical resection rate or successful conversion rate in the immunochemotherapy group was 48.3% (14/29), which was higher than that in the chemotherapy group (20.8%, 5/24), but lower than that in the neoadjuvant immunochemotherapy group for lung squamous cell carcinoma (60.8%, 93/153) [31]. More patients with more pCR in the immunochemotherapy group suggested that the addition of immunotherapy resulted in increased anti-tumor efficacy from a pathologic perspective. The surgical resection rates may be influenced by a combination of factors, including patient characteristics, tumor biology, and treatment strategies. As we could see, 40.0% of the patients underwent thoracotomy in the chemotherapy group, and 28.6% of the patients were converted from VATS to thoracotomy in the immunochemotherapy group, which suggests that neoadjuvant therapy may result in increased surgical difficulty. Lad et al. reported that the rate of pCR after chemotherapy regimen was 19% [32]. Our previous study revealed that the rate of pCR and MPR after neoadjuvant immunotherapy combined with chemotherapy was 30.0% and 40.0%, respectively [27]. The reason for the difference may be due to the heterogeneity in patients and treatment regimens.
No new or unexpected AEs were observed in our study. All of trAEs were manageable and tolerable. This was different from other researches focused on SCLC. CA184-156 study found that the rate of grade 3 to 4 AEs for chemotherapy and immunochemotherapy was 44% and 46%, respectively [33]. IMPOWER-133 study reported that the incidence of grade 3 and 4 AEs in the chemotherapy group was 56.1% with immunochemotherapy group 56.6%20. CASPIAN study showed that the incidence of grade 3 or 4 AEs in the chemotherapy and immunochemotherapy group was both 62%21. KEYNOTE-604 study found that in the chemotherapy and immunochemotherapy group, AEs were grade 3–4 in 76.7% and 74.9%, respectively [22]. Reasons why the AEs rate that our study was different from other studies may be the small sample size, the use of different immunotherapy regimens and heterogeneity of patients’ stage. Prophylaxes G-CSF was used, thus there was fewer grade 3/4 leukopenia. There were no patients with immune pneumonia in our study. Immunological pneumonia has occurred in several cases during the treatment of NSCLC in our center, but no interstitial pneumonia was found in this SCLC study. The preliminary consideration is that the total number of patients receiving immunotherapy for NSCLC is high. In this SCLC study, due to the short duration of the study and the small number of patients included, no occurrence of interstitial pneumonia was found in this study.
Our study possesses certain constraints. First, it was a retrospective study and our sample size was small. This may result in selection biases and reduce our study’s statistical power. Second, there was heterogeneity in patients and treatment regimens in our study. Finally, there was a brief postoperative follow-up in our study. This may affect our interpretation and judgment of survival outcomes.
In conclusion, neoadjuvant immunochemotherapy for patients with stage I–IIIB SCLC is feasible and safe with considerable therapeutic effect, as well as manageable AEs. Although immunochemotherapy was not significantly associated with prolonged DFS versus chemotherapy alone in patients with stage I–IIIB SCLC, it was associated with significant downstaging and increase the possibility of surgery. What’s more, further follow-ups are required to evaluate survival outcomes in patients with stage I–IIIB SCLC. And randomized controlled trials with larger scales are needed to test and verify our findings.
Author contributions
Linhai Zhu (Conceptualization, Data curation, Formal Analysis, Investigation, Visualization, Methodology, Writing- review & editing). Jiacong Liu (Conceptualization, Data curation, Formal Analysis, Investigation, Visualization, Methodology, Writing - original draft). Xuhua Huang (Conceptualization, Data curation, Investigation, Visualization, Methodology, Writing- review & editing). Jian Hu (Conceptualization, Funding acquisition, Investigation, Resources, Supervision, Validation). All authors contributed to the article and approved the submitted version.
Funding
This research was supported by the National Key Research and Development Program of China (2022YFC2407303), the Zhejiang Province Major Science and Technology Special Program Project (grant numbers 2020C03058), the Zhejiang Province Lung Tumor Diagnosis and Treatment Technology Research Supported by the Center (grant numbers JBZX-202007).
Data availability
The data of the current study are available from the corresponding author on reasonable request.
Declarations
Ethical Statement
This study was approved by the Clinical Research Ethics Committee of the First Affiliated Hospital, Zhejiang University School of Medicine (2022 IIT No. 1166), and done in accordance with the Declaration of Helsinki (as revised in 2013) and Good Clinical Practice Guidelines. Written informed consent was obtained from patients so that we could acquire and use required information from their medical record in our hospital.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Linhai Zhu, Jiacong Liu and Xuhua Huang contributed equally to this work.
Contributor Information
Linhai Zhu, Email: Linhai_zhu@zju.edu.cn.
Jian Hu, Email: dr_hujian@zju.edu.cn.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data of the current study are available from the corresponding author on reasonable request.