Radiation therapy (RT) plays an important role in the management of locally advanced non–small-cell lung cancer (NSCLC). In the neoadjuvant (preoperative) setting, thoracic RT with concurrent chemotherapy (CT) can be an effective means for downstaging mediastinal disease and improving the likelihood of complete resection. In the adjuvant (postoperative) setting, RT may decrease the risk of locoregional recurrence for patients with high-risk disease such as pathologic N2 involvement and/or positive margins. Modern techniques of radiation treatment planning and delivery have improved the safety profile and efficacy of thoracic RT.

Neoadjuvant Concurrent CT and RT

In patients with stage IIIA, locally advanced NSCLC, neoadjuvant RT with concurrent CT (CT/RT) can play an important role in downstaging mediastinal disease and increasing the likelihood of an R0 resection. Neoadjuvant CT/RT has been studied systematically in the past several decades in the cooperative group setting. The Southwestern Oncology Group (SWOG) conducted a phase-II study (SWOG 88-05) of preoperative RT to 45 Gy with two cycles of concurrent “EP50/50” chemotherapy (cisplatin 50 mg/m² on days 1, 8, 29, and 36 and etoposide 50 mg/m² on days 1–5 and days 29–33) in 126 patients with stage IIIA/B NSCLC with either biopsy-proven positive N2 or N3 nodes, or T4 primary lesions.¹ Patients with a response or stable disease proceeded to surgery. The clinical response rate to neoadjuvant therapy was 59%, and the resectability rate was 85% for patients with stage IIIA and 80% for patients with stage IIIB disease. The pathologic complete response rate was 21%. With a median follow-up of 2.4 years, the 3-year overall survival was 26%. While the locoregional recurrence rate was a promising 11%, the distant recurrence rate was 61%. Of interest, the strongest predictor of survival was clearance of mediastinal nodal (N2) disease by neoadjuvant treatment. The study reported a 3-year overall survival of 44% in patients with complete clearance of nodal disease (ypN0) and 18% in patients without nodal clearance (ypN+). Outcomes were particularly poor in patients with N3 disease by the presence of contralateral lymph nodes with a 3-year overall survival of 0%. However, the 3-year overall survival in patients with N3 disease due to the presence of supraclavicular lymph nodes was 35%. Treatment was relatively well tolerated, but concurrent CT/RT did result in grade 4 toxicity in 13% of patients and grade 5 toxicity in 10% of patients. However, this trial was conducted in an era when RT was delivered using fluoroscopic planning instead of modern computed tomography-based approaches.

Given the promising results of SWOG 88-05, this trimodality approach was compared against concurrent CT/RT alone in the Intergroup 0139 trial. This trial randomized 396 patients with initially unresectable T1-3, pathologic N2 NSCLC to preoperative concurrent CT/RT followed by surgery versus concurrent CT/RT alone.² Treatment in the trimodality arm was similar to the SWOG 88-05 regimen and included 45 Gy of preoperative RT with two cycles of concurrent EP50/50 followed by surgery 3 to 5 weeks afterwards, but added two cycles of consolidative CT after surgery. The treatment in the CT/RT alone arm consisted of radiation to 61 Gy with two cycles of concurrent EP50/50 and two cycles of consolidative CT. In the trimodality arm, there was an 18% pathologic complete response rate and clearance of mediastinal nodal disease (ypN0) occurred in 47% of patients. With a median follow-up of 22.5 months, in comparison to concurrent CT/RT alone, trimodality therapy significantly improved local recurrence (10% vs. 22%; p = 0.002) and 5-year progression-free survival (22% vs. 11%; p = 0.017). Despite the addition of two cycles of consolidative CT, distant metastatic recurrence remained a significant problem in both arms (37% vs. 42%; p = 0.32). There was no significant difference in overall survival between trimodality therapy and concurrent CT/RT alone with a 5-year overall survival of 27% versus 20% and median survival of 23.6 months versus 22 months (p = 0.24). In an unplanned subset analysis of patients by nodal status after preoperative therapy, patients with ypN0 disease (47% of patients) had a 5-year overall survival of 41% compared to 24% for patients with ypN+ disease (42% of patients). Patients who did not proceed to surgery after neoadjuvant CT/RT had a much worse prognosis with a 5-year overall survival of 8%. The lack of a statistically significant difference in survival between the two arms may have been due to a higher rate of treatment-related mortality in the trimodality arm (7.9% vs. 2.1%). In particular, patients receiving pneumonectomy in the trimodality arm of this study had a 26% (14 of 54 patients) mortality rate compared to 1% for patients undergoing lobectomy (Table 87-1). In an unplanned analysis, patients undergoing lobectomy had a 5-year overall survival of 36% compared to 18% (p = 0.002) in a matched group of patients undergoing concurrent CT/RT alone. In contrast, patients undergoing pneumonectomy did not have a significantly different 5-year overall survival (22% vs. 24%) compared to a matched group of patients undergoing concurrent CT/RT.

The results of the Intergroup 0139 trial suggest that trimodality therapy improves local control and progression-free survival, but does not significantly improve overall survival. However, the high mortality rate for patients who underwent pneumonectomy, particularly complex right pneumonectomy, may have diminished the potential survival benefit due to the addition of surgery. In a hypothesis generating subset analysis, it appeared that patients who were eligible to undergo a lobectomy after neoadjuvant CT/RT may have had the biggest benefit in overall survival from trimodality therapy compared to concurrent CT/RT alone.

Interestingly, since the publication of the results of Intergroup 0139, multiple retrospective series of patients treated with a pneumonectomy as part of trimodality therapy have shown lower mortality rates. For instance, a series of 73 patients from Brigham and Women’s Hospital and Dana-Farber Cancer Institute who underwent pneumonectomy (62% left-sided and 38% right-sided) after preoperative RT demonstrated 30- and 100-day mortality rates of 6% and 10%, respectively.³ The mortality rate was 11% in the 28 patients who underwent complex pneumonectomy versus 9% in the 45 patients who underwent simple pneumonectomy, and 4% in the 45 patients who underwent left pneumonectomy versus 18% in the 28 patients who underwent right pneumonectomy. Other single institutional studies have demonstrated comparable mortality rates of 5% to 15%,^4,5 which are lower than the 26% mortality rate seen in the Intergroup 0139 study. Thus, trimodality therapy that includes pneumonectomy may be feasible with acceptable toxicity rates in centers with a high case volume.

With the development of more modern RT techniques and based on positive experiences reported at the University of Maryland,^6,7 the Radiation Therapy Oncology Group (RTOG) conducted a Phase II, multi-institutional pilot study (RTOG 0229) of dose escalated preoperative RT to 61.2 Gy in 34 fractions with concurrent weekly carboplatin and paclitaxel prior to lobectomy or pneumonectomy in patients with resectable stage III disease.⁸ The primary endpoint of the study and the reason for testing a high preoperative RT dose was to increase the mediastinal nodal clearance rate from 47% as observed in the Intergroup 0139 trial to 50%–70%. Given the higher preoperative RT dose compared to Intergroup 0139 (~33% higher), the study mandated placement of a muscle flap on the bronchial stump to buttress the bronchus and minimal intravenous fluid use in the immediate postoperative period (<1500 mL per day for the first 4 days). The study also encouraged diuretic therapy in the postoperative period (furosemide 20 mg twice daily).

The eligibility criteria included stage T1-3, N2-3 (excluding patients with supraclavicular nodes, performance status 0–1, and FEV1 > 2 L or predicted postoperative FEV1 > 0.8 L. The study enrolled 60 patients with 57 patients eligible for analysis. The neoadjuvant treatment was delivered as intended in the majority of patients with 91% receiving neoadjuvant CT and RT as per protocol.

Thirty-seven (65%) of the 56 patients who completed neoadjuvant CT/RT underwent surgery (34 lobectomies, 3 pneumonectomies), iresulting in 74% R0 and 26% R1 resections. An additional six patients had surgical staging of the mediastinal nodes after neoadjuvant therapy, and overall 63% (27/43) achieved complete mediastinal nodal clearance (ypN0). With a median follow-up of 24.4 months, the median OS was 26.6 months with a 2-year OS of 54%. The median PFS was 12.9 months with a 2-year PFS of 33%. In an unplanned subgroup analysis of ypN0 versus ypN+ versus no surgery, the 2-year OS estimates were 75%, 52%, and 23%, respectively (p < 0.0002) and the 2-year PFS estimates were 56%, 26%, and 8%, respectively (p < 0.0001). The incidence of grade 3 postoperative pulmonary complications was 14% (5/37), and there was one postoperative grade 5 event due to pulmonary edema in a patient who underwent pneumonectomy.

Thus, this RTOG 0229 study demonstrated that pulmonary resection can be safely performed after neoadjuvant CT with full-dose RT in the multi-institutional setting with a higher rate of complete mediastinal nodal clearance compared to historical controls from Intergroup 0139. The study also demonstrated a low incidence of postoperative mortality overall with careful surgical techniques and postoperative care.

Neoadjuvant Concurrent CT and RT versus Neoadjuvant CT with Adjuvant RT

A potential alternative to neoadjuvant concurrent CT/RT is neoadjuvant CT alone followed by resection and postoperative RT as described in Chapter 88. While there are no data from randomized trials directly comparing the two neoadjuvant approaches, a German randomized trial does provide some insights. In this German study, 524 patients with stage IIIA and IIIB NSCLC were treated with three cycles of neoadjuvant CT (cisplatin and etoposide) and then randomized to neoadjuvant concurrent CT/RT followed by surgery or immediate surgery followed by adjuvant RT.⁹ In essence, the trial compares different sequencing of the three treatment modalities after initial neoadjuvant CT: either neoadjuvant concurrent CT/RT followed by resection or neoadjuvant CT alone followed by resection and postoperative adjuvant RT. The concurrent neoadjuvant CT/RT consisted of three cycles of carboplatin and vindesine with hyperfractionated, twice daily RT (total dose 45 Gy with 1.5 Gy delivered twice a day followed by a 24 Gy boost if inoperable or R1/R2 resection), which are approaches not commonly used in the United States. Patients in the neoadjuvant CT alone arm received adjuvant RT consisting of 54 Gy in 30 daily fractions after R0 resection or 68.4 Gy in 38 fractions after R1/R2 resection or in inoperable patients. With a median follow-up of 70 months, this study demonstrated no significant difference between the neoadjuvant CT followed by neoadjuvant CT/RT arm versus the neoadjuvant CT alone followed by resection and adjuvant RT arm in 5-year overall survival (18% vs. 21%; p = 0.97) or progression-free survival (14% vs. 16%; p = 0.087). The therapy in both arms was relatively well tolerated with a low rate of treatment-related deaths (5.8% vs. 6.4%, respectively). For the patients who underwent pneumonectomy (35%), the mortality rate was not significantly different between the neoadjuvant CT followed by CT/RT arm versus the neoadjuvant CT alone followed by resection and adjuvant RT arm (14% vs. 6%); moreover, the mortality rate in both arms was lower than that in the Intergroup 0139 study. Among the patients who underwent resection, neoadjuvant concurrent CT/RT was superior to neoadjuvant CT alone followed by resection and adjuvant RT; complete (R0) resection rates were 75% versus 60% (p = 0.008), and mediastinal downstaging rates were 46% versus 29% (p = 0.02).

This study demonstrated that the addition of neoadjuvant concurrent CT/RT to initial neoadjuvant CT does not impact survival compared to a strategy of sequencing RT after neoadjuvant CT and surgery, but the concurrent neoadjuvant CT/RT approach does result in increased downstaging of both the primary and mediastinal diseases. In unplanned subset analyses of these patients, there was no increase in overall survival for patients with either mediastinal downstaging or complete resection, but the small numbers of patients in these subgroups likely underpowered this analysis. Furthermore, this study’s results must be interpreted with caution since the hyperfractionated RT approach utilized in the neoadjuvant CT/RT arm is not commonly used in the United States, and both arms received three cycles of upfront neoadjuvant CT. Thus, while there is no conclusive evidence regarding the optimal neoadjuvant approach, it does appear that neoadjuvant concurrent CT/RT may have an important role in improving the likelihood of mediastinal nodal clearance and achieving R0 resections, which are both surrogate outcomes that may be associated with improved survival.

Neoadjuvant Concurrent CT and RT for Superior Sulcus Tumors

Neoadjuvant concurrent CT/RT may play a particularly important role in the management of superior sulcus tumors. A multi-institutional phase II trial led by SWOG (Intergroup 0160/SWOG 9416) demonstrated the efficacy of neoadjuvant CT/RT in 95 patients with T3-4, N0-1 NSCLC involving the superior sulcus.¹⁰ The neoadjuvant concurrent CT/RT was identical to the Intergroup 0139 study (45 Gy and concurrent cisplatin and etoposide), but radiation treatment planning was performed using three-dimensional (3D) computed tomography rather than two-dimensional (2D) techniques. Of the 95 patients, 83 (87%) were able to undergo thoracotomy and an impressive 76 (92%) of these patients had a complete resection. Additionally, 63% of the patients undergoing surgery had a pathologic complete response or minimal microscopic residual disease. With a median follow-up of 82 months, the 5-year overall survival was 44% and the 5-year overall survival in patients who underwent a complete resection was 54%. Treatment was well tolerated with treatment-related deaths observed in 2.7% of patients. Regarding patterns of failure, local failure was seen in only 17 (18%) of 95 patients, and distant recurrence occurred in 26 (27%) of 95 patients, with brain metastases the most common site of failure. Overall, this study demonstrated that neoadjuvant concurrent CT/RT for patients with superior sulcus tumors produced excellent resection rates and outcomes with minimal toxicity.

Neoadjuvant Concurrent CT and RT Summary

Prospective trials of neoadjuvant concurrent CT/RT followed by surgery have demonstrated that this approach is well tolerated and results in improved local control and progression-free survival compared to definitive concurrent CT/RT alone. In these studies, clearance of mediastinal nodal disease by neoadjuvant therapy was an important favorable prognostic factor for overall survival. The Intergroup 0139 randomized trial demonstrated a survival benefit for patients who underwent lobectomy after neoadjuvant therapy, but a higher mortality rate was seen for patients who underwent pneumonectomy (particularly right-sided complex pneumonectomy). However, multiple single institution centers have demonstrated lower mortality rates with pneumonectomy after neoadjuvant therapy, suggesting that this approach may be feasible at centers with high surgical volume and experience with the trimodality approach. Additionally, the Phase II RTOG 0229 trial demonstrated that dose escalation of preoperative RT is feasible and well-tolerated using modern RT techniques and careful surgical technique, and results in high likelihood of mediastinal nodal clearance. However, further study is required and high dose preoperative RT approaches should be conducted only at surgical centers with significant experience with this approach. Despite the excellent local control rates seen with trimodality therapy, distant recurrence remains a significant problem, and underscores the need to identify better systemic agents.

Neoadjuvant RT and CT Recommendations

It is our practice at Brigham and Women’s Hospital and Dana-Farber Cancer Institute to offer neoadjuvant concurrent CT/RT to patients with stage IIIA NSCLC who are good candidates for surgery. Surgery is also sometimes considered for select patients with stage IIIB disease (such as those who are young, have an excellent performance status, have a low bulk of nodal disease and achieve nodal downstaging following neoadjuvant therapy). Successful delivery of trimodality therapy requires close interdisciplinary communication and coordination of care between the thoracic surgeon, medical oncologist, and radiation oncologist. Typically, we recommend neoadjuvant concurrent CT/RT and the CT options include the SWOG/Intergroup 0139 regimen of cisplatin and etoposide for patients who are in good health or weekly carboplatin and paclitaxel for older patients or those with comorbidities as described in Chapter 88. A few weeks following completion of neoadjuvant therapy, restaging studies such as chest computed tomography or positron emission tomography (PET) are obtained and resection is performed approximately 4 to 6 weeks after completion of RT in eligible candidates. Patients who are deemed to be “marginally resectable” at initial trimodality consultation undergo a carefully timed reevaluation toward the end of neoadjuvant concurrent CT/RT. Specifically, about 1 to 2 weeks before the completion of neoadjuvant therapy, restaging studies are obtained and reviewed by the thoracic surgeon to assess for tumor response and resectability. Patients eligible for resection complete the neoadjuvant treatment course and then proceed to surgery, whereas those judged to be unresectable continue concurrent CT/RT to a higher dose without a treatment break. Consolidation CT after surgery is an option for patients who tolerate trimodality therapy well.