In patients with non‑small cell lung cancer who have undergone curative‑intent surgery with incomplete (R1 or R2) resection, does adjuvant radiotherapy, chemotherapy, or combined chemoradiotherapy improve overall survival, disease‑free survival, and local control compared with observation or alternative adjuvant approaches?

Management of Incomplete Resection (R1/R2) in NSCLC

For patients with R1 (microscopic) resection, adjuvant platinum-based chemotherapy should be administered first, followed by sequential radiotherapy if local recurrence risk is high; for R2 (macroscopic) resection, treat with concurrent chemoradiotherapy as you would for unresectable stage III disease. 1

R1 (Microscopic Positive Margins) Resection

Primary Treatment Approach

• Adjuvant chemotherapy is the cornerstone of treatment and should be prioritized based on randomized data showing improved recurrence-free survival, even though overall survival benefit was not definitively proven in the limited R1-specific trial data 1

• Administer platinum-based doublet chemotherapy for 3-4 cycles within 12 weeks of surgery in patients with good performance status 1, 2, 3

• The pattern of recurrence after R1 resection shows that approximately 75% of patients experience recurrence, but only one-third are local (intrathoracic) recurrences, with the majority being distant metastases—this supports prioritizing systemic chemotherapy over radiotherapy 1

Role of Adjuvant Radiotherapy for R1

• Sequential radiotherapy should be added after chemotherapy completion only when local recurrence risk is particularly high, as assessed by the operating surgeon 1

• No studies directly examined whether adjuvant radiotherapy improves survival after R1 resection, and a 2005 systematic review of 13 retrospective cohort studies found no clear evidence of survival benefit 1

• Concurrent postoperative chemoradiotherapy is not recommended due to poor compliance with adjuvant chemotherapy and increased toxicity requiring dose reductions 1

• The most recent high-quality evidence from the National Cancer Database (2003-2006) showed that combined chemotherapy and radiotherapy improved 5-year survival compared to surgery alone across all stages: stage pI (44% vs 35%), stage pII (33% vs 21%), and stage pIII (30% vs 12%) 4

Re-resection Consideration

• If reoperation is likely to achieve R0 resection, this is a reasonable option, though there is no clear evidence that re-resection improves survival over adjuvant therapy 1

R2 (Macroscopic Positive Margins) Resection

Treatment Paradigm Shift

• R2 resection should be viewed as a large biopsy rather than a therapeutic resection with curative intent 1

• These patients should be treated with definitive concurrent chemoradiotherapy using the same protocols as for unresectable stage III disease 1

• There is no benefit to debulking procedures for locally advanced lung cancer 1

Evidence for Combined Modality Therapy

• The single randomized trial (1979-1985) of 164 patients with R1/R2 resection (84% R1, 16% R2) showed improved recurrence-free survival with chemotherapy added to radiotherapy (P=0.004), though overall survival was not significantly improved 1

• More recent National Cancer Database analysis demonstrated that combined chemotherapy and radiotherapy improved 5-year survival for stage pIII patients with R2 resection (30% vs 12% with surgery alone) 4

Critical Decision-Making Algorithm

Step 1: Confirm Resection Status

• R1 (microscopic positive margins) → Proceed to Step 2
• R2 (macroscopic residual disease) → Treat as unresectable stage III with concurrent chemoradiotherapy 1

Step 2: For R1 Resection - Assess Patient Fitness

• Good performance status (ECOG 0-1) → Platinum-based doublet chemotherapy 1, 2, 3
• Poor performance status (ECOG 2+) or significant comorbidities → Single-agent chemotherapy 3

Step 3: For R1 Resection - Evaluate Local Recurrence Risk

High-risk features include:

• N2 nodal involvement 1
• Multiple positive margins 1
• Central tumor location 1
• Surgeon's assessment of inadequate clearance 1

If high local recurrence risk → Add sequential radiotherapy after chemotherapy completion 1

If low local recurrence risk → Chemotherapy alone may suffice 1

Specific Treatment Regimens

Chemotherapy Options

• Cisplatin-based doublets (cisplatin/etoposide or cisplatin/vinorelbine) are standard 1
• Administer for 3-4 cycles starting within 12 weeks of surgery 1, 2, 3

Radiotherapy Parameters

• When indicated, deliver radiotherapy sequentially after chemotherapy completion 1
• Use modern intensity-modulated radiation therapy (IMRT) technique 5
• Dose of 60 Gy in 2.0 Gy fractions is standard for definitive treatment 5

Common Pitfalls to Avoid

• Do not give concurrent postoperative chemoradiotherapy due to increased toxicity and poor compliance 1

• Do not treat R2 resection with adjuvant therapy alone—these patients require definitive concurrent chemoradiotherapy 1

• Do not administer radiotherapy alone for R1 resection, as this showed worse survival than surgery alone in stage pI patients (26% vs 35%, P=0.04) 4

• Do not delay chemotherapy beyond 12 weeks from surgery 1, 2, 3

• Do not assume all R1 resections require radiotherapy—the majority of recurrences are distant, not local 1

Expected Outcomes

• R1 resection has significantly worse 5-year survival compared to R0 resection across all stages: stage pI (37% vs 62%), stage pII (29% vs 41%), and stage pIII (19% vs 33%) 4

• Combined chemotherapy and radiotherapy for R1 resection improves outcomes but does not restore survival to R0 levels 4

• The frequency of R1/R2 resection in pN2 stage III NSCLC ranges from 25% with thorough preoperative staging to 35% with poor preoperative staging 1

Multidisciplinary Discussion Requirement

• All R1/R2 resection cases must be discussed in multidisciplinary tumor board to weigh locoregional relapse risk against systemic relapse risk for individualized treatment planning 1

• The decision should involve thoracic surgeon, medical oncologist, and radiation oncologist 5