NSCLC Study Highlights Need for Adjuvant Trials in Early-Stage Disease

New research is sounding the alarm on patients with early-stage non–small cell lung cancer (NSCLC)—clinical stage 1a tumors that are 2 cm or smaller (T1N0)—not being included in trials for adjuvant therapies.

Published today in JAMA Oncology,¹ the investigators of a secondary analysis of data from the Cancer and Leukemia Group B (CALGB) 140503 trial (NCT00499330), also known as ALLIANCE, highlight that visceral pleural invasion (VPI), a known poor prognostic factor in NSCLC,² may be to blame; this is when tumors invade beyond the elastic layer of visceral pleura and have potential to invade an adjacent lung lobe.³ Even among these patients with early-stage NSCLC, the extent of parenchymal resection did not have an impact on their disease-related outcomes in this analysis. The primary outcome of interest for CALGB 140503 was disease-free survival (DFS).

The authors noted that the controversy surrounding upstaging patients’ tumors to T2 following VPI findings per parenchymal resection spurred this subanalysis. Overall in CALGB 140503, they added, “sublobar resections were associated with similar oncological outcomes to those after lobar resection.” Also, they noted, few studies have examined potential associations between VPI with smaller tumors and patient survival, “although VPI is known to be associated with worse survival in patients with stage I lung cancer.”

In this subanalysis of the CALGB 140503, 73.6% of patients had an ECOG performance status of 0, and just 16.2% had tumors with visceral pleural invasion | Image Credit: Vitalii Vodolazskyi - stock.adobe.com

There were 679 patients in their analysis; more than half (57.4%) were women, and the median age was 67.8 years (range, 37.8-89.7). Most patients (73.6%) had an ECOG performance status of 0 (P = .09). Just 16.2% of the overall study population had tumors with VPI (T2); 81.2% of patients had T1 tumors, or no VPI. They were enrolled between June 2007 and March 2017 from 83 clinical sites, and the median follow-up was 7 years.

Looking at the authors’ results, the patients with T1 tumors were highly likely to fare better overall compared with the patients with T2 tumors, according to several outcomes of interest:

• 5-year DFS:
  • Patients with T1 tumors: 65.9% (95% CI, 61.9%-70.2%)
  • Patients with T2 tumors: 53.3% (95% CI, 44.3%-64.1%) (P = .02)
• Disease recurrence:
  • Patients with T1 tumors: 27.6%, with patients with locoregional only recurrence faring better vs those with distant-only recurrence (10.8% vs 14.6%)
  • Patients with T2 tumors: 41.6%, with patients with locoregional only recurrence faring better vs those with distant-only recurrence (15.0% vs 23.9%)
• 5-year recurrence-free survival:
  • Patients with T1 tumors: 73.1% (95% CI, 69.2%-77.1%)
  • Patients with T2 tumors: 58.2% (95%CI, 49.2%-68.8%) (P = .01)

DFS rates did not significantly differ between patients who had lobectomy or sublobar resection, echoing overall CALGB 140503 findings:

• Patients with T1 tumors: 5-year DFS was 66.3% in those had lobectomy vs 65.6% in those who underwent sublobar resection
• Patients with T2 tumors: 5-year DFS was 53.1% in those had lobectomy vs 53.5% in those who underwent sublobar resection

Among the study population, the most common tumor size was between 1.0 and 1.5 cm (P = .11), 41.2% were current smokers vs 49.8% who were former smokers (P = .42), the most common lung histology was adenocarcinoma (63.2%) (P = .22), and the most common tumor locations were the right upper lobe (35.8%) and the left lower lobe (27.2%) (P = .32). Pathological N stage was N04 in 95.3%, indicating no regional lymph node metastasis; N15 in 3.4%, indicating peribronchial or ipsilateral hilar region, or both, metastasis; and N26 in 1.3%, indicating ipsilateral mediastinal and subcarinal lymph node metastases.

Overall survival was 80.5% in those with T1 tumors and 74.7% in those with T2 tumors; 10 patients died within 3 months of their surgery due to treatment-related adverse events.

“The observed higher risk of distant recurrence raises the question of whether these patients should receive adjuvant therapy,” the study authors wrote. “Nearly all patients at this early stage of lung cancer are traditionally excluded from adjuvant trials.” They noted this is because previous research in patients with stage I disease has demonstrated the harm of chemotherapy to these patients and that it may be ineffective.

They concluded that even though their findings are limited because CALGB 140503 did not consider pathological staging in its survival analysis, their relevance should become more prominent as lung cancer screening expands.

References

1. Altorki N, Wang X, Damman B, et al. Recurrence of non–small cell lung cancer with visceral pleural invasion: a secondary analysis of a randomized clinical trial. JAMA Oncol. Published online August 1, 2024. doi:10.1001/jamaoncol.2024.2491

2. Seok Y, Jeong JY, Lee E. Extent of visceral pleural invasion and the prognosis of surgically resected node‐negative non‐small cell lung cancer. Thorac Cancer. 2017;8(3):197-202. doi:10.1111/1759-7714.12424

3. Weerakkody Y. Visceral pleural invasion. Radiopaedia. January 17, 2024. Accessed July 31, 2024. https://radiopaedia.org/articles/visceral-pleural-invasion?lang=us#:~:text=Visceral%20pleural%20invasion%20is%20a,adjacent%20lobe%20of%20the%20lung