ABSTRACT: Locally advanced non–small-cell lung cancer is a heterogeneous group of diseases encompassing both stage IIIA and IIIB disease. The treatment options vary, including surgery, chemotherapy, neoadjuvant concurrent chemoradiation, definitive chemoradiation, radiation, and various combinations of the above. Optimal therapy for each patient group is controversial; however, previous trials have shown efficacy of various treatments for different stages. Surgery as initial therapy is beneficial for patients with stage T3, N1 or T3-4, N0-1 disease due to satellite lesions within the same lung. Chemotherapy should be used for diseases minimally involving the mediastinal lymph nodes, whereas concurrent induction chemoradiation is a good option for bulky nodal disease prior to planning a resection. Concurrent definitive chemoradiation or definitive radiation should be reserved for patients who are not candidates for a surgical resection. Most importantly, the treatment strategy for stage IIIA/IIIB disease should involve a multimodality approach individualized to the patient’s disease stage, age, underlying medical conditions, and performance status.
Despite recent therapeutic advances, lung cancer continues to be one of the leading causes of cancer-related mortality. Of the various histologic subtypes, non–small-cell lung cancer (NSCLC) is the most common—accounting for approximately 85% of all lung cancers—and will be the focus of this article. In general, the treatment of lung cancer may include surgery, radiation therapy, systemic therapy (eg, chemotherapy with or without targeted therapy), or a combination of the above. Surgery continues to offer the best chance of long-term cure. The initial treatment of stage I and II NSCLC usually entails surgical resection, whereas stage IV disease is primarily treated with systemic agents, in light of the lack of curative potential with surgery and/or radiation therapy alone. It is locally advanced NSCLC, including stage IIIA and IIIB disease, that continues to pose a therapeutic dilemma, given its heterogeneous nature.
The tumor-node-metastasis (TNM) staging guidelines for NSCLC established in 1997 (see Table 1) staged IIIA disease as encompassing tumors ranging from T3, N1 to T3, N2, whereas stage IIIB encompassed tumors that were more locally advanced, ranging from T4, N0 to T4, N2/N3 (Table 2). The distinction between the two subsets of stage III disease is important, as surgical resection can be used for stage IIIA disease, whereas stage IIIB disease is usually initially addressed nonsurgically.
As of the fall of 2009, a new lung cancer staging system has been in place (Table 3). While the N description has not changed, some modifications have been made in the T and M categories. The data presented in this paper are based on the old lung cancer staging system; however, the recent changes do not affect the information and recommendations provided herein.
Underlying the decision regarding any treatment planning is consideration of the patient’s performance status, comorbid medical conditions, age, cardiopulmonary status, and preferences.
The various therapeutic options available for the initial treatment of locally advanced NSCLC include surgery, neoadjuvant chemotherapy or concurrent chemoradiation followed by surgery, and definitive concurrent chemoradiation. Each option will be discussed separately.
As noted above, surgery is an important consideration for any patient diagnosed with stage I/II NSCLC. It is also an important consideration for stage III NSCLC. However, the extent of local disease as well as the extent and location of nodal involvement might preclude surgery as an initial treatment option. The bulkiness of nodal involvement is an important distinction for operable disease. Patients with bulky stage IIIA/IIIB disease are usually considered inoperable, whereas those with nonbulky disease might be surgical candidates. Bulky disease is defined in various ways, but most often is described as lymph nodes > 2 cm in the short-axis diameter on chest computed tomography, disease in a group of lymph nodes, or involvement of more than two lymph node stations. In general, surgery may be indicated as initial treatment for T3-4, N0-1 disease, including cases where satellite nodules are present within the same lobe or ipsilateral lung.
T3, N0-1 tumors usually invade the chest wall or are within 2 cm of the carina, and are not associated with mediastinal lymph node involvement. Resection with negative margins is possible for these tumors despite surgeries that are usually complex. There is no clear evidence of a role for neoadjuvant chemotherapy in this setting.
The Neoadjuvant/Adjuvant Taxol (paclitaxel) Carboplatin(Drug information on carboplatin) Hope (NATCH) trial[3,4] showed feasibility and tolerability of neoadjuvant chemotherapy for early-stage NSCLC including T3, N1 disease. In this phase III trial, 624 patients with stage I, II, or T3, N1 disease were enrolled into three arms: (1) 212 received surgery only, (2) 201 received three cycles of preoperative carboplatin and paclitaxel(Drug information on paclitaxel) followed by surgery, and (3) 211 underwent surgery with three cycles of adjuvant carboplatin and paclitaxel planned. The initial results showed a possible improvement in overall survival in patients with T3, N1 disease who received neoadjuvant chemotherapy, compared to those who received adjuvant therapy vs surgery alone. However, a more recent presentation at the 2009 annual meeting of the American Society of Clinical Oncology showed no difference in disease-free survival among the three arms. In addition, there was no difference in overall survival at 5 years. Most current practices recommend resection as first-line treatment in T3, N1 disease. Adjuvant chemotherapy is also recommended.
Surgery also has a role in the initial treatment of T3-4, N0-1 disease due to satellite lesions within the same lobe of the primary tumor or ipsilateral lung. A retrospective analysis by Port et al indicated that patients with satellite lesions within the same lobe of the primary tumor have a 5-year survival rate resembling that of patients with stage IB or II disease after resection. The 5-year survival for all patients with a resected intralobar satellite lesion was 47.6%. Thus, surgery should be considered appropriate initial treatment followed by adjuvant chemotherapy for patients with such disease.
Neoadjuvant chemotherapy is an important consideration for any patient presenting with locally advanced NSCLC. Survival is poor in patients with N2 disease who undergo surgery alone, as they have a high chance of recurrence and distant relapse following resection. The benefits of neoadjuvant chemotherapy include better patient tolerability of therapy, the potential for treating micrometastatic disease, and decreased tumor size to improve potential surgical resection.
Neoadjuvant chemotherapy was first studied as a therapeutic option beginning in the late 1980s, when the data regarding its efficacy were mixed. Trials in the early 1990s, including those of Rosell et al,[6,7] Pass et al, and Roth et al, showed an improvement in overall survival in patients with stage III disease receiving neoadjuvant chemotherapy compared to surgery alone. Depierre et al conducted a larger trial than the earlier studies and found no survival advantage from neoadjuvant chemotherapy. The chemotherapy used in most of these trials were older regimens, which have since been replaced. More recent trials[11,12] have used gemcitabine(Drug information on gemcitabine) (Gemzar)- and platinum-based therapy in the preoperative setting and have found not only a good tolerability of the therapy, but also a benefit to neoadjuvant therapy.
The Bimodality Lung Oncology Team (BLOT) trial assessed the feasibility of perioperative paclitaxel and carboplatin in patients with early-stage IB–IIIA NSCLC. In this phase II trial, 94 patients were enrolled with an intention to receive two cycles of neoadjuvant chemotherapy with paclitaxel and carboplatin, followed by surgery and three additional adjuvant cycles of chemotherapy. After induction therapy, 53 of 94 patients had a significant response and 81 patients underwent complete surgical resection. A total of 90 patients successfully received the two cycles of neoadjuvant therapy; however, only 45% received adjuvant therapy.
Based on the results of the BLOT study, the Southwest Oncology Group (SWOG) S9900 was a phase III trial designed to compare neoadjuvant chemotherapy with surgery alone. A total of 354 patients were enrolled in the study. The neoadjuvant group received three cycles of carboplatin and paclitaxel, whereas the other arm underwent surgery alone. The trial was closed early since adjuvant therapy became the standard of care. However, of the 133 patients treated with neoadjuvant therapy, 95% were able to achieve complete resection of their tumor, compared with only 88% of patients in the surgery-alone group. Overall survival was 47 months with neoadjuvant therapy, compared to 40 months for surgery alone. Progression-free survival was 31 months for neoadjuvant therapy, compared to 20 months for surgery alone. This trial showed the feasibility and tolerability of neoadjuvant chemotherapy, with improvement in overall survival.
Neoadjuvant chemotherapy is advisable in patients with disease minimally involving the mediastinal lymph nodes or a mass that is locally invasive where a possible decrease in size will make it amenable to resection.