Residency · Residency · Cardiothoracic Surgery

Neoadjuvant and Adjuvant Therapy in Lung Cancer

Overview

Multimodal therapy integrating systemic treatment with surgery improves outcomes in resectable NSCLC. The traditional approach of surgery followed by adjuvant chemotherapy for stage II-III disease has been transformed by a paradigm shift: neoadjuvant immunotherapy (with or without chemotherapy) is now standard for resectable stage IB-IIIA NSCLC. Pathologic complete response (pCR) and major pathologic response (MPR) are emerging surrogate endpoints for survival.

Adjuvant Chemotherapy

Indications

Adjuvant cisplatin-based chemotherapy is the standard of care for completely resected stage II and IIIA NSCLC. It is considered for high-risk stage IB tumors, defined by features such as tumor size greater than 4 cm, poorly differentiated histology, lymphovascular invasion, visceral pleural invasion, or incomplete lymph node sampling. Adjuvant chemotherapy is not recommended for stage IA.

Evidence Base

The LACE meta-analysis (2008) pooled data from 5 RCTs involving 4,584 patients and demonstrated a 5.4% absolute improvement in 5-year survival with cisplatin-based adjuvant chemotherapy, with the greatest benefit in stage II-III disease, no benefit in stage IA, and uncertain benefit in stage IB. JBR.10 showed a 15% absolute survival benefit at 5 years for stage II disease using cisplatin plus vinorelbine versus observation. ANITA demonstrated an 8.6% absolute survival benefit at 5 years using cisplatin plus vinorelbine for stage IB-IIIA. CALGB 9633, which studied carboplatin plus paclitaxel for stage IB only, showed no overall survival benefit.

Landmark Adjuvant Chemotherapy Trials

Standard Regimens

The most evidence-based regimen is cisplatin plus vinorelbine. Alternatives include cisplatin plus pemetrexed (for non-squamous histology), cisplatin plus gemcitabine, and cisplatin plus docetaxel. Four cycles are administered within 6-8 weeks of surgery. Carboplatin may be substituted for patients who cannot tolerate cisplatin.

Adjuvant Targeted Therapy

The ADAURA trial demonstrated that adjuvant osimertinib (an EGFR TKI) dramatically improves disease-free survival in stage IB-IIIA EGFR-mutant NSCLC (HR 0.17 for stage II-IIIA), with overall survival benefit confirmed at long-term follow-up. Three years of treatment is administered after adjuvant chemotherapy if indicated. All resected NSCLC should undergo molecular testing to identify actionable targets. For ALK-positive tumors, adjuvant alectinib is under investigation, with the ALINA trial showing a DFS benefit.

<image>Timeline diagram showing sequencing of surgery, adjuvant chemotherapy, and adjuvant targeted therapy (osimertinib) for EGFR-mutant resectable NSCLC</image>

Neoadjuvant Chemotherapy

Rationale

Neoadjuvant chemotherapy treats micrometastatic disease early, allows assessment of tumor chemosensitivity in vivo through pathologic response, provides better drug delivery to the tumor via the intact blood supply, and identifies patients with rapidly progressive disease who would not benefit from surgery.

Evidence

Meta-analyses show a 5% absolute improvement in 5-year OS with neoadjuvant cisplatin-based chemotherapy, similar in magnitude to adjuvant chemotherapy. No head-to-head trial has shown superiority of neoadjuvant versus adjuvant chemotherapy. The neoadjuvant approach allows assessment of pathologic response and does not increase surgical morbidity when surgery occurs within 4-6 weeks of completing chemotherapy.

Neoadjuvant Immunotherapy: The New Standard

CheckMate 816 (Nivolumab + Chemotherapy)

This phase III trial compared neoadjuvant nivolumab plus platinum doublet chemotherapy for 3 cycles versus chemotherapy alone, followed by surgery, in resectable stage IB (4 cm or greater) to IIIA NSCLC. The pCR rate was 24% with nivolumab plus chemotherapy versus 2.2% with chemotherapy alone. The MPR rate was 36.9% versus 8.9%. Event-free survival was significantly improved (HR 0.63). There was no increase in surgical complications or delays. Higher pCR and MPR rates were seen in tumors with PD-L1 of 1% or greater. This is now an FDA-approved regimen for resectable NSCLC (stage IB 4 cm or greater to IIIA).

KEYNOTE-671 (Pembrolizumab Perioperative)

This trial evaluated neoadjuvant pembrolizumab plus chemotherapy for 4 cycles, then surgery, then adjuvant pembrolizumab for 13 cycles, in stage II-IIIB (N2) resectable NSCLC. It demonstrated significant improvement in both EFS and OS, with a pCR rate of 18.1% versus 4.0%. This was the first perioperative immunotherapy trial to show an overall survival benefit. It is now an FDA-approved perioperative regimen.

AEGEAN (Durvalumab Perioperative)

Neoadjuvant durvalumab plus chemotherapy followed by adjuvant durvalumab showed significant improvement in pCR and EFS. It is FDA-approved.

Landmark Neoadjuvant Immunotherapy Trials

Neoadjuvant-Adjuvant (Perioperative) Approach

Emerging consensus favors perioperative immunotherapy (neoadjuvant plus adjuvant) over neoadjuvant alone. KEYNOTE-671 provides the strongest evidence for this approach. The duration of the adjuvant immunotherapy component is up to 1 year.

<image>Forest plot comparing pathologic complete response rates across major neoadjuvant immunotherapy trials: CheckMate 816, KEYNOTE-671, AEGEAN, and CheckMate 77T</image>

Surgical Considerations After Neoadjuvant Therapy

Restaging

Repeat CT chest and PET-CT are obtained after completing neoadjuvant therapy. If N2 disease was present initially, repeat mediastinal staging (EBUS or mediastinoscopy) is performed. Brain MRI is obtained if not recently performed. Response is assessed using RECIST criteria for radiographic response.

Operative Planning

Surgery should be performed within 4-8 weeks of the last neoadjuvant cycle. Tissue planes may be altered by the treatment response, with fibrosis and inflammation. Desmoplastic reaction can make hilar dissection more challenging. Pneumonectomy rates are not increased after neoadjuvant immunotherapy (unlike older chemoradiation data). Complete resection (R0) rates remain high (greater than 80%) after neoadjuvant immunotherapy.

Pathologic Response Assessment

Pathologic complete response (pCR) indicates no viable tumor cells in the resected specimen and lymph nodes. Major pathologic response (MPR) indicates 10% or fewer viable tumor cells remaining. Both pCR and MPR correlate with improved long-term survival. Immune-related pathologic changes include necrosis, fibrosis, granulomatous inflammation, and tertiary lymphoid structures.

Adjuvant Radiation Therapy

Post-Operative Radiation Therapy (PORT)

The original PORT meta-analysis (1998) showed a detrimental effect of PORT in N0-N1 disease. The Lung ART trial (2022), which studied modern conformal PORT for N2 disease, showed no improvement in DFS or OS and increased cardiopulmonary toxicity. PORT is no longer recommended as routine therapy for completely resected N2 disease. It may be considered for R1/R2 resections (positive margins).

Neoadjuvant Chemoradiation

SWOG 8805 established the role of induction chemoradiation for superior sulcus tumors. For potentially resectable N2 disease, induction chemoradiation followed by surgery remains an option, though induction chemo-immunotherapy is increasingly preferred. Higher complete resection rates are achieved when given before surgery for locally advanced disease.

<image>Algorithm for perioperative therapy selection in resectable NSCLC based on stage, PD-L1 status, and molecular markers including EGFR and ALK</image>

Molecular Testing in Resectable NSCLC

All resected NSCLC (especially non-squamous) should undergo molecular profiling. Key actionable targets include EGFR mutations (exon 19 deletion, L858R) for adjuvant osimertinib, ALK rearrangements for adjuvant alectinib (emerging data), and other targets (ROS1, BRAF, MET, RET, KRAS G12C) that inform surveillance and treatment of recurrence. PD-L1 testing guides immunotherapy decisions, though benefit is seen across PD-L1 subgroups.

Clinical Pearls

Neoadjuvant chemo-immunotherapy is now the standard of care for resectable stage II-IIIA NSCLC — purely adjuvant chemotherapy alone is no longer optimal for these stages. Pathologic complete response after neoadjuvant immunotherapy is a powerful prognostic marker, and detailed pathologic response assessment should always be requested. Surgery after neoadjuvant immunotherapy is safe and feasible with no increase in complications compared to upfront surgery. Molecular testing of every resected NSCLC is mandatory because EGFR-mutant tumors derive enormous benefit from adjuvant osimertinib. PORT for N2 disease is no longer supported by modern evidence (Lung ART), and radiation should not be reflexively added. Perioperative immunotherapy (neoadjuvant plus adjuvant) is likely superior to neoadjuvant alone based on KEYNOTE-671 OS data. Patients with rapidly progressive disease during neoadjuvant therapy should be re-evaluated because progression on immunotherapy may indicate aggressive biology or driver mutations.

References

• Pignon JP et al. "Lung Adjuvant Cisplatin Evaluation (LACE): a pooled analysis." J Clin Oncol. 2008.
• Forde PM et al. "Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer (CheckMate 816)." N Engl J Med. 2022.
• Wakelee HA et al. "Perioperative pembrolizumab for early-stage non-small-cell lung cancer (KEYNOTE-671)." N Engl J Med. 2023.
• Wu YL et al. "Osimertinib in resected EGFR-mutated non-small-cell lung cancer (ADAURA)." N Engl J Med. 2020.
• Le Pechoux C et al. "Postoperative radiotherapy versus no postoperative radiotherapy in patients with completely resected non-small-cell lung cancer and proven mediastinal N2 involvement (Lung ART)." Lancet Oncol. 2022.
• NCCN Clinical Practice Guidelines: Non-Small Cell Lung Cancer. Version 2024.

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