Locally advanced non–small cell lung cancer

Introduction

Locally advanced non−small cell lung cancer (NSCLC), most commonly defined as stage III by the American Joint Committee on Cancer (AJCC) staging classification, accounts for roughly one third of newly diagnosed NSCLC, and there is considerable heterogeneity among these cases. According to the AJCC eighth edition, stage IIIA (T1-T2 N2, T3-T4 N1, T4 N0) disease involves ipsilateral mediastinal lymph nodes or more extensive primary tumors, stage IIIB disease (T1-T2 N3, T3-T4 N2) involves contralateral mediastinal or supraclavicular lymph nodes or larger primary tumors with ipsilateral mediastinal involvement, and stage IIIC (T3-T4 N3) involves both larger primary tumors and contralateral mediastinal or supraclavicular lymph nodes. Stage IIIA NSCLC can be further divided into cases that are unresectable and those potentially resectable and can also include cases where pathological staging after a surgical resection reveals occult mediastinal nodal disease. Stage IIIB and IIIC NSCLC are generally classified as unresectable.

Because of the heterogeneity shown in locally advanced NSCLC, treatment strategies have long been a subject of controversy, and clinical trial evidence is commonly limited by differences in patient populations. In light of this, there is no “one-size-fits-all” approach and a multidisciplinary evaluation involving radiation oncology, medical oncology, and thoracic surgery is recommended. However, despite optimal treatment through modern clinical trials and recent advances in therapy, the prognosis for patients with stage III NSCLC remains limited, with 5-year survival rates of <30%–40% and median overall survival (OS) of 28 months. ^, Although these rates are significantly better than historical controls, improvements are still needed.

This chapter focuses on the management of unresectable locally advanced NSCLC. We also briefly cover surgically resectable disease; however, this topic is more comprehensively discussed elsewhere (see Chapters 4 and 5 ). For many years, the cornerstone of standard-of-care therapy in unresectable locally advanced NSCLC has been concurrent chemoradiation. Over the years, there have been improvements in therapy, including the recent addition of consolidation immunotherapy. This chapter highlights the incremental improvements in both radiation and chemotherapy administration, as well as the recent advances in immunotherapy, which have translated into improved outcomes for this challenging disease.

Treatment of patients with potentially resectable disease

All patients with diagnosed or suspected NSCLC should undergo a thorough staging workup, which includes radiographic and, in most cases, pathological assessments. Diagnostic recommendations for staging include computed tomography (CT) of the chest and upper abdomen (including adrenals), fluorodeoxyglucose–positron emission tomography (FDG PET)/CT scan, and magnetic resonance imaging of the brain. Pathological mediastinal lymph node evaluation is also generally recommended, most commonly through endobronchial ultrasonography, endoscopic ultrasonography, or mediastinoscopy. Further details of the diagnostic workup are discussed in Chapter 2 .

Once tumor staging and assessment of the patient’s physiological reserve are obtained, the next key consideration is determining surgical resectability ( Fig. 7.1 ). For patients with stage IIIA disease who are amenable to initial surgical resection (including cases with occult mediastinal nodal involvement), adjuvant systemic therapy is recommended. However, considerable variations exist in practice and selection for this patient group. For patients with T4 N0 or T3-4 N1 disease who otherwise meet criteria for resection, surgery is the preferred approach, along with adjuvant chemotherapy. The management of stage IIIA N2 disease can be less straightforward and remains controversial. A further review of the surgical considerations and a discussion of adjuvant chemotherapy and postoperative radiation therapy for resectable NSCLC are presented in Chapter 5 .

Early clinical trials have demonstrated a dramatic improvement in survival outcomes with the addition of neoadjuvant chemotherapy before resection. Rosell and colleagues reported results of a trial of 60 patients with stage IIIA NSCLC who were randomized to surgery either alone or with preoperative chemotherapy (3 cycles of cisplatin 50 mg/m ² , ifosfamide 3 g/m ² , and mitomycin 6 mg/m ² , given every 3 weeks). Median OS was significantly better for the chemotherapy group versus surgery alone, at 26 months compared with 8 months ( P < 0.001). In a similar randomized study from Roth and colleagues of 60 patients with stage IIIA NSCLC given surgery alone or surgery with perioperative chemotherapy (cisplatin, etoposide, and cyclophosphamide), an interim analysis after early termination showed median OS of 64 months for the chemotherapy group compared with 11 months for surgery alone ( P < 0.008).

The further addition of radiation therapy along with preoperative chemotherapy was explored in a randomized trial by the German Lung Cancer Cooperative Group. The control arm received 3 cycles of cisplatin and etoposide chemotherapy, followed by surgery and then radiation therapy. The intervention arm received the same 3 cycles of preoperative chemotherapy but, before surgery, also underwent concurrent twice-daily radiation with carboplatin and vindesine. Although patients treated on the intervention arm had improved rates of pathological response (60% vs. 20%; P < 0.0001) and mediastinal downstaging (46% vs. 29%; P = 0.02), this did not translate into a survival benefit, with median OS of 15.7 versus 17.6 months for all patients ( P = 0.97) and 32.4 versus 33.0 months for patients who underwent resection ( P = 0.54). It was noted that patients on the intervention arm who underwent pneumonectomy had a relatively high rate of treatment-related mortality at 14%.

RTOG 9039 was a phase 3 trial in which 396 patients with stage IIIA (N2) NSCLC were treated with radiation therapy (45 Gy in 1.8-Gy fractions over 5 weeks) concurrently with chemotherapy using cisplatin (50 mg/m ² on days 1, 8, 29, and 36) and etoposide (50 mg/m ² on days 1–5 and 29–33). Patients with no disease progression were then randomized to either surgical resection or continued radiation therapy to 61 Gy. All patients then received an additional 2 cycles of cisplatin/etoposide. Progression-free survival (PFS) favored surgical resection (median PFS, 12.8 vs. 10.5 months; P = 0.017), although median OS was not significantly different between the two groups (23.6 vs. 22.2 months; P = 0.24). Analyses of 5-year survival favored those who had surgical resection, although this was not statistically significant (27.2% vs. 20.3%; P = 0.10). An exploratory analysis showed improved median OS for patients who underwent lobectomy versus a matched cohort on chemoradiation alone, but not for patients who underwent pneumonectomy. This can be explained by higher postoperative mortality due to pneumonectomy treatment, with mortality occurring in 7.9% of patients in the surgical arm (mostly after pneumonectomy) compared with 2.1% of patients who had chemoradiation alone.

After chemoradiation alone please include the following: The Lung ART trial was a randomized, phase 3, superiority trial comparing mediastinal PORT to no PORT in patients with NSCLC after complete resection and pathologically proven N2 involvement. A total of 501 patients were enrolled and randomly assigned to receive PORT (252 patients) or no PORT (249 patients). The 3-year disease-free survival was higher than expected in both groups (47% with PORT vs. 44% without PORT) and the median disease-free survival was 30.5 months for PORT and 22.8 months without PORT neither of which was statistically significant. The PORT group had higher rates of toxicity including pneumonitis (5% vs. <1%), lymphopenia (4% vs 0) and late cardiopulmonary toxicity (11% vs 5%). The authors concluded that PORT was not associated with an increased disease-free survival and thus could not be recommended as the standard for Stage IIIA patients with N2 disease.

In summary, the available evidence suggests that select patients with N2 disease may be treated with neoadjuvant therapy followed by surgical resection. This is an active area of research with rapidly expanding systemic treatment options in the neoadjuvant setting as well. For patients who do receive neoadjuvant radiation therapy, this approach preferably must have a lobectomy planned rather than pneumonectomy. Patients who are most likely to benefit are those with only one mediastinal nodal station involved, with treatment performed in a center with a low perioperative mortality rate. However, options for patients with N2 disease remain controversial since a clear benefit compared with definitive chemoradiation has not been established. Therefore patients with potentially resectable stage III NSCLC should be managed by a multidisciplinary team that incorporates best surgical judgment and best available clinical data.

Pancoast tumors

Tumors involving the superior sulcus (commonly termed Pancoast tumors, after the radiologist who described this clinical entity) are a small subset of locally advanced lung cancer that present unique treatment challenges. Pancoast tumors are frequently characterized by invasion into adjacent structures, including vertebrae, ribs, brachiocephalic vein, subclavian artery, the brachial plexus, and/or stellate sympathetic ganglion. Involvement of the stellate ganglion can result in Horner syndrome (ptosis, miosis, and anhidrosis), which is a hallmark presentation of these tumors ( Fig. 7.2 ). Compression of the nerves or vasculature of the upper extremity is associated with the so-called “thoracic outlet syndrome,” which can result in pain, paresthesia, weakness, and changes in perfusion of the affected extremity.

The management of Pancoast tumors depends on the extent of invasion and lymph node involvement, ultimately affecting surgical resectability. For tumors with extensive T4 invasion or N2-3 involvement, resection is typically not feasible and a definitive concurrent chemoradiation approach is suggested (see discussion later on unresectable advanced NSCLC). For T3-4 N0-1 superior sulcus tumors, a number of studies have demonstrated the feasibility and efficacy of preoperative chemoradiation therapy followed by surgical resection. In the SWOG 9416 trial, 110 patients with T3-4 N0-1 NSCLC of the superior sulcus received cisplatin (50 mg/m ² on days 1, 8, 29, and 36) and etoposide (50 mg/m ² on days 1–5 and 29–33) concurrently with radiation therapy (45 Gy in 1.8-Gy fractions over 5 weeks). Patients with stable disease or response underwent attempted resection. In total, 104 patients (95%) completed induction chemoradiation and 88 (80%) underwent subsequent surgery, with 83 (76%) having complete resection. Pathological complete response or minimal microscopic disease was noted in 61/110 patients (56%). Postoperative mortality was 1.8%, 5-year survival was 44%, and local relapse occurred in only 10 patients (9%). These results compared favorably with historical studies, and this strategy remains a standard of care for Pancoast tumors.

An alternative approach to potentially resectable Pancoast tumors is the use of neoadjuvant chemotherapy followed by surgical resection, with radiation given postoperatively. One rationale for such an approach is that a high rate of positive margins may be observed during resection, and the ability to deliver postoperative radiation to address the residual disease is limited after induction chemoradiation. In a single-institution retrospective analysis of 102 patients treated with multimodality therapy for superior sulcus NSCLC, this approach showed comparable survival outcomes with a possible lower risk of complications. Of 53 patients treated with induction chemoradiation, 5-year OS was 47.1% compared with 46.7% for 34 patients treated with induction chemotherapy and postoperative radiation. This was despite the pathological complete response rate being significantly higher in the chemoradiation group (38% vs. 3%; P < 0.001). It was noted that chemoradiation therapy was associated with a higher postoperative reintubation rate (13% vs. 0%; P = 0.03).

Radiation therapy considerations for unresectable disease

Thoracic radiation therapy (RT) has been an important component of treatment for patients with unresectable NSCLC dating back to the 1950s. Historically, the thoracic RT technique initially consisted of plain film radiography for target localization and field design; this protocol was associated with fairly large treatment volumes and high radiation doses to surrounding normal structures. However, technological improvements have allowed more precise delivery of RT to the tumor while limiting dose to normal organs, including the heart, esophagus, and lung, thus resulting in improved outcomes.