Treatment Options and Emerging Therapies

Overview of NSCLC Treatment

Historically, non-small cell lung cancer (NSCLC) treatment involved three modalities: surgery, radiation therapy and chemotherapy. In the last two decades, the treatment landscape of NSCLC has greatly expanded with the development of targeted therapies, immune checkpoint blockers/inhibitors (ICBs), new surgical and radiotherapeutic techniques, and new neoadjuvant and perioperative strategies. In combination with more efficient screening practices, this progress has led to significantly improved survival rates (see Overview). This Section provides an overview of treatment strategies by TNM Stage and discusses the individual treatment modalities in more detail. The therapeutic space of NSCLC is rapidly evolving, with novel agents gaining approval and existing agents receiving expanded indications. Please consult the current Food and Drug Administration’s Drug Approvals and Databases for the most up-to-date information on approved drugs and their indications.

A simplified overview of NSCLC treatment strategies is presented in FIGURE 3-1. It is important to note that NSCLC is curable if detected at an early stage – ideally Stage I. Stage II and, in rare cases, Stage III disease may also be cured with surgery. The goal of treatment for nonresectable Stage III disease and Stage IV disease is to prolong survival and maintain quality of life.

Stage I NSCLC is treated with surgery or stereotactic ablative radiotherapy (SABR; also known as stereotactic body radiation therapy, or SBRT), with the aim of destroying or removing the tumor (Figure 3-1a, upper panel); no adjuvant treatment (i.e., treatment given after the main therapy) is required. For resectable Stage IB-IIIA cancer with EGFR or ALK changes, TKIs that target these oncogenes (osimertinib, alectinib) may be given as adjuvant therapy after surgery (Figure 3-1b). The approach to tumors of Stage II and III may include one of three strategies (Figure 3-1a, lower panel): neoadjuvant treatment (ie, treatment given before the main therapy to improve its success rate) with chemotherapy and an ICB followed by surgery; perioperative treatment with chemotherapy and an ICB, with continued treatment with the ICB following the surgery; and up-front surgery followed by adjuvant treatment with chemotherapy with or without an ICB. For unresectable Stage III disease (Figure 3-1c, upper panel), the initial approach is often a combination of chemotherapy and radiotherapy, and adjuvant treatment consists of the ICB durvalumab (for cancers without a driver mutation) or targeted therapy against the cancer’s driver mutation. For Stage IV disease without targetable driver mutations, an ICB or a combination of ICBs with or without chemotherapy may be tried, especially if the tumor’s PD-L1 expression profile favors it (Figure 3-1c, middle panel). If ICBs are contraindicated in this setting, the only option is platinum doublet chemotherapy as the initial approach, and maintenance chemotherapy as adjuvant treatment (Figure 3-1c, bottom panel). For Stage IV disease with a targetable mutation, both the initial and adjuvant treatment involve targeted therapy against the mutation.

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Surgical Options

Surgery is the main treatment option for patients with Stage I and Stage II disease and selected patients with Stage IIIA disease. The basic criterion for resectability is whether the tumor can be completely excised while preserving enough lung function for the patient to breathe adequately after surgery. In addition to the overall stage, the lymph lode involvement (N) category should be considered; N0 and N1 disease generally considered resectable but N2 disease (especially if bulky or multistation) may require additional neoadjuvant therapy, as determined by a multidisciplinary team. Additionally, it is important to assess the patient's preoperative lung function, taking into consideration any comorbidities, before the patient is deemed fit for surgery. Patients with a forced expiratory volume (FEV)₁ of 60% or more are generally considered fit for surgery. Those with FEV₁ below 60% (and especially <30%) require additional testing to assess cardiopulmonary function; their risk of perioperative mortality may be substantially increased, of which they should be informed and offered a more limited resection, non-surgical therapy and/or preoperative and/or postoperative pulmonary rehabilitation. Pulmonary function assessment is particularly important in patients with comorbidities such as Chronic obstructive pulmonary disease (COPD) and current smokers; the latter should be counseled to stop smoking immediately.

Surgery for lung cancer involves excision of the tumor in the lung and removal of locoregional lymph nodes to ensure complete removal of the cancer. Surgery may be anatomical (i.e., resection of the lung according to the branching of the pulmonary airways) or nonanatomical (in which the target tumor determines the extent of resection). Common types of surgical resection are shown in Figure 3-2. In most patients with NSCLC, lobectomy (ie, removal of a single lobe; see Figure 3-2C) is the preferred option. Sleeve lobectomy (lobectomy which removes a part of the bronchus, after which the free ends of the remaining bronchus are reconnected; see Figure 3-2D) is often required for centrally located tumors. Pneumectomy (see Figure 3-2E), or removal of the entire lung, is typically reserved for patients in whom bronchoplasty as part of sleeve lobectomy cannot be performed. Finally, in sublobar resection, only a part of a lung lobe is removed. There are two forms of sublobar resection: segmentectomy, which is anatomical (Figure 3-2B) and wedge resection, which is nonanatomical (Figure 3-2A). Because it was traditionally viewed as oncologically inferior to lobectomy, sublobar resection used to be reserved for patients who could not tolerate a lobectomy due to poor lung function. It is now understood that sublobar resection may be a useful option in patients with small tumors with no nodal involvement. Regardless of the extent of resection, all lung cancer surgeries must include a comprehensive assessment of lymph nodes for confirmation of staging.

Lung cancer surgery has historically been performed via open thoracotomy, i.e., the cutting of the chest call to access the thoracic cavity. However, in recent years open thoracotomy is increasingly being replaced by thoracoscopy (Figure 3-3). The two major forms of thoracoscopic surgery are video-assisted thoracoscopic surgery (VATS) and robotic-assisted thoracoscopic surgery (RATS), both of which are minimally invasive techniques. In VATS, a thoracoscope and special surgical instruments are inserted via small incisions into the thoracic cavity; the thoracoscope sends a video feed to monitors in the operating room allowing the surgeon to perform the resection. Robust data from large prospective series and randomized trials have demonstrated that, compared to thoracotomy surgery, VATS decreases post-operative pain, complication risk, and length of hospital stay with equivalent oncologic efficacy. Although the evidence is still evolving, current data suggests that RATS, which uses robotic surgical systems (e.g., the DaVinci robot) to assist the surgeons, has comparable short- and long-term safety and efficacy to VATS, while providing a less steep learning curve and better operative flexibility.

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Radiation Therapy

Radiation therapy, or radiotherapy, involves the use of high-energy beams of ionizing radiation (X-rays, gamma rays, or electrons) to damage the DNA of cancer cells, impairing their ability to divide and/or destroying them. Radiotherapy is an important but globally underutilized modality for NSCLC treatment: an estimated 77% of lung cancer patients have an indication for its application. Radiotherapy can be applied with both curative and palliative intent. Conventional radiotherapy uses wide radiation fields on the tumor and its neighboring lymph nodes. However, since ionizing radiation also damages non-cancerous cells, conventional radiotherapy has largely been replaced by newer methods that allow more precise radiation delivery to target lesions and affected lymph nodes. This was made possible by specific technological advances, in particular the development of four-dimensional CT (4DCT; enabling precise measurement of the tumor motion and position during the treatment) and improvements in patient immobilization.

Two such precise forms of radiotherapy are now routinely used in NSCLC treatment: Stereotactic ablative radiotherapy (SABR), also known as stereotactic body radiation therapy (SBRT), (SABR/SBRT) and intensity-modulated radiotherapy (IMRT). In SABR, ablative doses of ionizing radiation are delivered in a small number (1-5) number of fractions (individual treatment session). For patients with Stage I-IIA disease who are medically inoperable or refuse surgery, SABR has become the standard of treatment and is curative in a large percentage of cases, although outcomes are worse than surgery with appropriate lymph node examination. In oligometastatic Stage IV disease, SABR has also demonstrated efficacy for improving progression-free survival (PFS) through the destruction of metastases. For nonresectable Stage III NSCLC, the current standard of care is concurrent chemotherapy and radiotherapy. In this setting, IMRT has demonstrated significant benefit, particularly for patients with large tumor volumes. This technique uses multiple radiation beams of different intensity, allowing the total dose to be spatially sculpted to deliver the optimal dose to the tumor while sparing, to the extent possible, to organs at risk, such as the heart. Evidence suggests that heart-sparing effects are responsible for the improvements in overall survival (OS) associated with IMRT.

Chemotherapy Regimens

Chemotherapy has historically been the main treatment for solid cancers of advanced (inoperable) stage, including NSCLC. In 1995, a meta-analysis from the Non-small Cell Lung Cancer Collaborative Group found a significant improvement in survival with chemotherapy as an adjuvant treatment following surgery or radiotherapy, and as an add-on to supportive care in patients with NSCLC. Broadly, two types of chemotherapy drugs are used in NSCLC treatment: platinum-containing agents (cisplatin and carboplatin) and non-platinum-containing agents (e.g., pemetrexed, docetaxel, gemcitabine, vinorelbine). A meta-analysis from 2005 demonstrated that platinum-based regimens were superior to non-platinum-based regimens at improving the 1-year survival rate, and platinum-based agents are generally preferred in patients who can tolerate them. In the era of targeted agents and ICBs, chemotherapy is often combined with these modalities for primary treatment or a neoadjuvant or adjuvant strategy.

Platinum-containing agents efficiently bind to DNA and induce DNA damage; they are toxic to all rapidly proliferating cells, which is the basis for their oncologic efficacy. However, since they also affect normal tissues, they are associated with gastrointestinal toxicity, nephrotoxicity, neurotoxicity, ototoxicity and myelosuppression. Cisplatin is slightly more efficacious than carboplatin for the treatment of lung cancer but is associated with less toxicity (except myelosuppression). For resectable Stage II and III NSCLC, platinum-based chemotherapy regimens may be used as part of a neoadjuvant or perioperative strategy (often in combination with an ICB), or as adjuvant treatment after surgery.

For locally advanced and metastatic NSCLC, chemotherapeutic regimens that combine a platinum compound with a non-platinum agent (“platinum doublet” regimens) may be used. Non-platinum agents commonly used in platinum doublet regimens for NSCLC include: pemetrexed (a folate antimetabolite used for nonsquamous NSCLC), gemcitabine (a pyrimidine nucleoside prodrug), the taxanes docetaxel and paclitaxel (including nab-paclitaxel, an albumin-bound-stabilized nanoparticle formulation of paclitaxel with improved solubility), and vinorelbine (a vinca alkaloid). For Stage III disease, platinum doublet chemotherapy delivered concurrently with radiotherapy is the standard of care; in this setting, consolidation chemotherapy does not provide further benefit. For many patients with Stage IV NSCLC, oncogene-targeted therapy or immunotherapy have replaced chemotherapy as the first-line treatment of choice. However, 60% or more of patients with NSCLC are negative for common driver mutations (EGFR mutations or ALK rearrangements), and two-thirds of these patients have a PD-L1 tumor proportion score of less than 50%. In the absence of other driver mutations, these patients are candidates for first-line treatment with platinum doublet chemotherapy.