Lung Cancer: Treatment

Mark M. Fuster

While overall survival for patients diagnosed with lung cancer remains poor (16%–18% 5-year survival), clinical and basic research over the last 10 to 15 years has led to the incorporation of adjuvant therapies as well as targeted therapies that may significantly improve outcomes in select groups of patients. The approach to treatment is now guided by a combination of histology (small-cell versus non–small cell) and stage of disease as well as the presence of molecular signatures that permit individualized therapy. The treatment approach also must take into consideration a patient’s general performance status and pulmonary function. The involvement of a multidisciplinary team (pulmonary, medical and radiation oncology, thoracic surgery, radiology, pathology, palliative care, and nursing specialists) in making integrated treatment decisions helps to provide state-of-the-art care. For non–small-cell lung cancer (NSCLC), the most basic decision at the time of diagnosis is whether the patient has early stage and potentially resectable disease (if the patient is deemed operable) or advanced-stage disease. For small-cell lung cancer (SCLC), the treatment approach depends on whether disease is limited versus extensive in anatomic extent, features that determine whether and how radiation is paired with chemotherapy as a basic form of treatment. Most of the chapter, and the following sections, will focus on NSCLC.

OPERABILITY, RESECTABILITY, AND ADJUVANT THERAPY FOR STAGE I AND STAGE II NSCLC

Surgical resection should be the first consideration for possible cure of stage I or stage II NSCLC. A patient must be operable to undergo resection. This assessment requires routine cardiovascular evaluation as well as pulmonary function and arterial blood gas testing. In general, a predicted postoperative forced expiratory volume in 1 second (FEV₁) or diffusing capacity of the lung for carbon monoxide (DLCO) of less than 40% indicates significant risk of perioperative complications or death following anatomic/lobar resections. DLCO is particularly important when imaging reveals diffuse parenchymal lung disease or in the setting of dyspnea on exertion. When pulmonary function results are marginal, cardiopulmonary exercise testing (with Vo₂ max < 15 mL/kg/min indicating increased perioperative risk) and/or quantitative ventilation–perfusion lung scanning may greatly assist in decision-making regarding operability. The lung scan occasionally may weight a decision toward surgery in a patient with marginal FEV₁ if a tumor-affected lobe contributes minimally to ventilation (or perfusion). In general, decisions must be individualized and often rely on integrating physiologic testing data.

Once a patient is deemed operable, the assessment of resectability depends upon stage. Stages I and II patients are candidates for resection. Following a lobar resection, adjuvant chemotherapy has been found to improve outcomes in patients with pathological stage II disease, although there is still no role for adjuvant therapy following resection of a lesion that is pathological stage IA. Finally, when compromised lung function precludes anatomic resection, a curative attempt with radiotherapy is generally employed, with sublobar resection (for stage IA) a less frequent approach. Radiotherapy for stage IA lesions has evolved to incorporate the use of higher-dose, hypofractionated programs (i.e., stereotactic body radiotherapy [SBRT]) that have markedly improved local control rates and curability. Studies on outcomes using SBRT for early stage disease are ongoing; however, more conventional radiation therapy for early stage lesions still produce significantly lower cure rates than that achieved by anatomic surgical resection. Following definitive therapy, surveillance imaging (i.e., CT thorax) is typically carried out twice yearly for 2 years, and yearly thereafter.

ADVANCED-STAGE NSCLC: CHEMOTHERAPY, RADIOTHERAPY, AND COMBINED-THERAPY APPROACHES

Stage IIIA disease is very heterogeneous. Most patients (e.g., with bulky N2/mediastinal adenopathy) are not resection candidates, and benefit most from a combination of chemotherapy and radiation. Standard chemotherapy is platinum-based and involves the use of two agents. Some stage IIIA patients (e.g., T3N1 superior sulcus tumor) may benefit from a “neoadjuvant” approach, wherein surgery following a good response to induction chemotherapy/radiation offers 5-year survival rates that exceed 30%. Neoadjuvant therapy, however, remains an area of investigation; for some patients, toxicity of this approach may be significant, and its use should generally remain within the context of a protocol. Occasionally, patients are found to have pathologic stage IIIA disease upon postoperative pathological review following lobar resection of what appeared to be clinical stage I or II; adjuvant chemotherapy has improved outcomes for such patients. Adjuvant radiotherapy may also be employed in patients found to have advanced-stage (III) disease at time of resection (or when resection results in positive surgical margins for any stage), with its major benefit a reduction in local–regional recurrence. For stage IIIB or stage IV disease, chemotherapy is the main form of therapy for patients with good-performance status. Concurrent delivery of chemotherapy and radiotherapy may be employed in the aggressive treatment of stage III patients, although toxicity may limit this approach. Sequential use of these modalities is a frequently used alternative. For stage IV NSCLC disease in patients with good-performance status, unless radiation is necessary for palliation, treatment is limited to chemotherapy. Stage IV disease is mostly noncurable with overall 5-year survival in the range of 10% to 15% for pathologic stage IV; however, patients with good-performance status may have 2-year survival rates of 30% to 40%. Survival in such patients may be further modified in responders to novel targeted therapies. Limited performance should be recognized, however, with appropriate and early institution of palliative measures to improve quality of life.

TARGETED TREATMENT FOR NSCLC: TAILORING THERAPY TO TARGETS AND THE INDIVIDUAL

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