Small cell lung cancer (SCLC) has long been considered "a graveyard for drug development" due to its aggressive nature and limited therapeutic options. However, a new study from Zhejiang University suggests that combining immunotherapy with chemotherapy before surgery could offer hope for patients with early-stage disease.
The retrospective single-arm clinical trial, conducted at the First Affiliated Hospital of Zhejiang University School of Medicine, enrolled 19 patients with stage I-IIIA SCLC who received neoadjuvant immunotherapy combined with chemotherapy between 2019 and 2021.
High Response Rates Enable Surgical Intervention
The study achieved an impressive objective response rate (ORR) of 84.2%, with 16 of 19 patients experiencing partial response and 3 achieving stable disease. No patients experienced complete response or progressive disease during neoadjuvant treatment.
"We found that the diameter of the lesion after 4 cycles of neoadjuvant therapy decreased more than after 2 cycles of treatment," the researchers noted, suggesting that extended treatment cycles may benefit patients without significant initial response.
The treatment protocol consisted of 2-4 cycles of immunotherapy combined with platinum-containing dual-drug chemotherapy. Immunotherapy options included camrelizumab 200 mg, nivolumab 3 mg/kg, pembrolizumab 100-200 mg, sintilimab 200 mg, or tislelizumab 200 mg, paired with platinum-based chemotherapy and paclitaxel regimens.
Significant Tumor Downstaging Observed
The neoadjuvant approach demonstrated remarkable efficacy in tumor downstaging. Before treatment, 84.2% of patients had stage II-III disease, but this decreased to 63.2% after treatment. The number of patients with T3, T2b, and T2a tumors decreased significantly, while those with T1 tumors increased.
Most notably, changes in lymph node involvement showed statistical significance (P<0.001), with decreases in N2 and N1 disease and increases in N0 status. Overall TNM stage changes were also statistically significant (P=0.015).
Surgical Outcomes and Pathological Response
Of the 19 patients, 10 ultimately underwent surgery, representing a 52.6% surgical rate. The median time from last neoadjuvant therapy to surgery was 27.5 days. Eight patients underwent minimally invasive surgery, while two required conversion to open surgery due to severe thoracic adhesions.
Surgical outcomes were encouraging, with 90% of patients achieving R0 resection and only one R1 resection. The median operation time was 131 minutes, with minimal blood loss (median 50 mL) and a median hospital stay of 15.5 days. No perioperative deaths occurred, with only one case of postoperative pyothorax.
Pathological Complete Response in 30% of Surgical Patients
Pathological evaluation revealed impressive results using the tumor regression grade (TRG) system. Three patients (30%) achieved TRG 0 (pathological complete response), one patient (10%) had TRG 1, and six patients (60%) had TRG 2-3. The major pathological response rate was 40%, while the pathological complete response rate reached 30%.
These rates compare favorably to historical data. As the researchers noted, "Lad et al. reported their pCR rate as 19%. The reason for the discrepancy may be due to the non-platinum chemotherapy regimen in the latter study."
Manageable Safety Profile
The treatment demonstrated a tolerable safety profile. Most adverse events were grade 1-2, with only two patients experiencing grade 3-4 events (one case each of anemia and constipation). No patients withdrew from treatment due to intolerable toxicity or progressive disease.
"None of the patients in our study had previously undocumented toxicities," the researchers reported, emphasizing the manageable nature of immune-related adverse events.
Implications for SCLC Treatment
SCLC accounts for approximately 13-15% of all lung cancers and is characterized by rapid growth, early metastasis, and poor prognosis. Limited-stage SCLC, representing about one-third of cases, has traditionally been treated with concurrent chemotherapy and radiotherapy, yielding 2-year survival rates below 50%.
The role of surgery in SCLC has been controversial since early trials in the 1960s-70s showed superior outcomes with radiotherapy compared to surgery alone. However, recent studies have suggested that surgery as part of multimodality therapy may benefit selected patients with early-stage disease.
The current study builds on emerging evidence that immunotherapy can enhance treatment outcomes in SCLC. Previous trials like IMPOWER-133 and CASPIAN demonstrated that immunotherapy plus chemotherapy as first-line therapy could significantly improve progression-free survival and overall survival compared to chemotherapy alone in extensive-stage disease.
Study Limitations and Future Directions
The researchers acknowledged several limitations, including the small sample size, retrospective design, absence of a randomized control group, and short postoperative follow-up. The heterogeneity of patients and treatment regimens may also limit statistical power and introduce selection bias.
"Larger, randomized controlled trials are required to confirm our findings," the authors concluded. "And whether a neoadjuvant therapy regimen gives a survival benefit should be confirmed by further follow-up."
Despite these limitations, the study provides encouraging preliminary evidence that neoadjuvant immunochemotherapy could expand surgical options for patients with early-stage SCLC, potentially improving outcomes in a disease with historically limited treatment success.
