Role of Induction Therapy: Surgical Resection of Non–Small Cell Lung Cancer After Induction Therapy

The role of postoperative radiotherapy (PORT) in patients with clinical stage III-N2 (cIII-N2) non-small cell lung cancer (NSCLC) treated with induction chemotherapy and surgical resection with persistent ypN2 disease is not well established.

We retrospectively reviewed a prospectively maintained database for patients with cIII-N2 NSCLC who underwent induction chemotherapy followed by resection (2004–2016). Exclusion criteria included induction radiotherapy, non–biopsy-confirmed cN2 disease, incomplete resection, ypN0/1, and nonanatomic resection. The primary outcome was locoregional recurrence (LR); secondary outcomes were disease-free survival (DFS), lung cancer–specific death (LCSD), and overall survival (OS). Associations between variables and outcomes were assessed using Fine and Gray competing risk regression for LR/LCSD and Cox proportional hazard models for survival.

Of the 501 patients identified with cIII-N2 disease, 99 met the inclusion criteria. Median follow-up was 25 months (range, 3-137 months). Sixty-nine patients (70%) received PORT. Sixty (61%) developed a recurrence: 3 (5%) with an initial isolated LR and 57 (95%) with an initial distant recurrence. On multivariable analysis, PORT was not associated with LR (HR, 0.51 [95% CI, 0.22-1.21], p = 0.13). PORT was also not associated with DFS (p = 0.6) or LCSD (p = 0.1). PORT was associated with improved 3-year OS (55% [95% CI, 42%-71%]) versus the no-PORT group (50% [95% CI, 34%-74%]) (p = 0.04).

PORT is not independently associated with decreased LR or improved DFS/LCSD in this patient population. Given that the predominant failure pattern was distant recurrence, future clinical trials should focus on adjuvant systemic therapies, which may decrease distant recurrences in ypN2 patients.

The objective of this study was to evaluate the treatment outcomes and prognostic factors of neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgical resection for non-small cell lung cancer (NSCLC) with N2 disease.

A retrospective review of patients with N2 disease who underwent neoadjuvant CCRT followed by surgery at our institution was performed and multivariate Cox regression analysis was used to determine the factors associated with survival outcomes.

From 1997 to 2013, 574 patients underwent curative-intent surgery after neoadjuvant CCRT for NSCLC with N2 disease. The mean age was 59 years (444 men, 77%). The extent of surgery included lobectomy in 418 patients (73%), pneumonectomy in 73 (13%), and sleeve resection in 25 (4.3%). Complete resection was obtained in 543 patients (95%). Postoperative complications and in-hospital mortality occurred in 199 patients (35%) and 21 (3.7%), respectively. Pathologic complete response was achieved in 72 patients (13%) and 304 (53%) experienced mediastinal clearance. With a mean follow-up of 36 months, median overall survival (OS) and recurrence-free survival (RFS) were 56 months and 18 months, respectively. The 5-year OS rates were 61% in ypN0, 49% in ypN1, and 35% in ypN2 (p = 0.001). The 5-year RFS rates were 45% in ypN0, 23% in ypN1, and 17% in ypN2 (p < 0.001). Older age, advanced pT stage, persistent N2, large cell carcinoma, and pneumonectomy were independent prognostic factors associated with worse OS and poorer RFS.

Neoadjuvant CCRT followed by surgery could be performed with acceptable early postoperative outcomes, satisfactory local control, and encouraging long-term survival. Care should be taken in selecting patients when necessitating pneumonectomy after neoadjuvant CCRT. Further efforts to improve outcomes in patients with persistent N2 disease are required.

Induction therapy is often recommended for patients with clinical stage IIIA-N2 (cIIIA/pN2) lung cancer. We examined whether postinduction positron emission tomography (PET) scans were associated with ypN2 disease and survival of patients with cIIIA/pN2 disease.

We performed a retrospective review of a prospectively maintained database to identify patients with cIIIA/pN2 non–small cell lung cancer treated with induction chemotherapy followed by surgery between January 2007 and December 2012. The primary aim was the association between postinduction PET avidity and ypN2 status; the secondary aims were overall survival, disease-free survival, and recurrence.

Persistent pathologic N2 disease was present in 61% of patients (61 out of 100). PET N2-negative disease increased from 7% (6 out of 92) before induction therapy to 47% (36 out of 77) afterward. The sensitivity, specificity, and accuracy of postinduction PET for identification of ypN2 disease were 59%, 55%, and 57%, respectively. Logistic regression analysis indicated that postinduction PET N2 status was not associated with ypN2 disease. Of the 39 patients with both pre- and postinduction PET N2-avidity, 25 (64%) had ypN2 disease. The 5-year overall survival was 40% for ypN2 disease versus 38% for N2-persistent disease (P = .936); the 5-year overall survival was 43% for postinduction PET N2-negative disease versus 39% for N2-avid disease (P = .251). The 5-year disease-free survival was 34% for ypN2-negative disease versus 9% for N2-persistent disease (P = .079).

Postinduction PET avidity for N2 nodes is not associated with ypN2 disease, overall survival, or disease-free survival in patients undergoing induction chemotherapy for stage IIIA/pN2 disease.

Radiotherapy is commonly used in induction regimens for patients with non–small cell lung cancer with operable mediastinal nodal disease, although evidence has not shown a benefit over induction chemotherapy alone. We compared outcomes between induction chemotherapy and induction chemoradiation using the National Cancer Data Base.

Induction radiation use and survival of patients who underwent lobectomy or pneumonectomy after induction chemotherapy for clinical T1-3N2M0 non–small cell lung cancer in the National Cancer Data Base from 2003 to 2006 were assessed using logistic regression, general linear regression, Kaplan–Meier, and Cox proportional hazard analysis.

Of 1362 patients who met study criteria, 834 (61%) underwent induction chemoradiation and 528 (39%) underwent induction chemotherapy. Lobectomy was performed in 82% of patients (n = 1111), and pneumonectomy was performed in 18% of patients (n = 251). Pneumonectomy was performed more often after induction chemoradiation than after induction chemotherapy (20% vs 16%, P = .04). Downstaging from N2 to N0/N1 was more common with induction chemoradiation compared with induction chemotherapy (58% vs 46%, P < .01), but 5-year survival of patients receiving induction chemoradiation and patients receiving induction chemotherapy was similar in unadjusted analysis (41% vs 41%, P = .41). In multivariable analysis, the addition of radiation to induction chemotherapy also was not associated with a survival benefit (hazard ratio, 1.03; 95% confidence interval, 0.89-1.18; P = .73).

Induction chemoradiation is used in the majority of patients with non–small cell lung cancer with N2 disease who undergo induction therapy before surgical resection, but it is not associated with improved survival compared with induction chemotherapy.

Although the standard treatment for patients with stage IIIA non-small cell lung cancer (NSCLC) is chemoradiotherapy, some patients are considered for trimodality therapy [TT]. We analyzed outcomes for stage IIIA NSCLC, treated with TT and compared them with concurrent chemoradiotherapy [con-CRT].

Patients treated between January 2007 and December 2011 were retrospectively analyzed. Not included were patients with sulcus superior tumors, unknown T/N-status, or recurrent disease after con-CRT followed by surgery. All patients were discussed at our multidisciplinary thoracic tumor board (MTB).

Mean Charlson Comorbidity Index was 2 for TT and con-CRT patients. TT patients were younger (median TT = 56 years vs. con-CRT = 62 years; p = 0.001) and had less advanced cN-stage (TT cN2 = 41% vs. 83% for CRT; p < 0.001). 44% of TT patients had T4-stage vs. 12% of con-CRT patients. Median RT dose was lower for TT (50 Gy vs. 66 Gy; p = 0.001) and median RT planning target volume (PTV) in TT and con-CRT patients was 525 cm³ and 655 cm³ (p = 0.010), respectively. The majority of TT patients had a lobectomy (23/32). Median follow-up was 30.3 months (95% CI = 18.7–41.9) for TT and 51 months (95% CI = 24.9–77.4) for con-CRT. Median overall survival was not reached for TT and was 18.6 months (95% CI = 12.8–24.4) for con-CRT (p = 0.001). For PTV </≥ 500 cm³, median OS for TT was not reached/33.9 months and 29.1/17.1 months for con-CRT. TT patients with cN0/1 had better survival than those receiving con-CRT (p = 0.015), but those with cN2 did not (p = 0.158). The 90-day mortality from start of RT was 0% (0/32) for TT and 1.7% (1/58) for con-CRT. 90-day post-operative mortality for TT was 3.1% (1/32, event unrelated to TT).

Selected patients with IIIA NSCLC treated with TT had favorable long-term survival with acceptable short-term mortality. These outcomes support the decision-making and function of our MTB/treatment team. The role of TT in cN2 disease and large tumors merits further evaluation.