A. Non–Small Cell Lung Carcinoma
Surgical resection offers the best chance for cure of NSCLC. Therefore, the initial approach to the patient is determined by answering two questions: (1) Is complete surgical resection technically feasible? (2) If yes, is the patient able to tolerate the surgery with acceptable morbidity and mortality? Clinical features that preclude complete resection include extrathoracic metastases or a malignant pleural effusion; or tumor involving the heart, pericardium, great vessels, esophagus, recurrent laryngeal or phrenic nerves, trachea, main carina, or contralateral mediastinal lymph nodes. Accordingly, stage I and stage II patients are treated with surgical resection where possible. Stage II and select cases of stage IB are additionally recommended to receive adjuvant chemotherapy. Stage IIIA patients have poor outcomes if treated with resection alone. They should undergo multimodality treatment that includes chemotherapy or radiotherapy, or both. Inoperable stage IIIA and stage IIIB patients treated with concurrent chemotherapy and radiation therapy have improved survival. Stage IV patients are treated with systemic therapy (targeted therapy, chemotherapy, or immunotherapy) or symptom-based palliative therapy, or both.
Surgical approach affects outcome. In 1994, the North American Lung Cancer Study Group conducted a prospective trial of stage IA patients randomized to lobectomy versus limited resection. They reported a threefold increased rate of local recurrence in the limited resection group (P = 0.008) and a trend toward an increase in overall death rate (increase of 30%, P = 0.08) and increase in cancer-related death rate (increase of 50%, P = 0.09), compared with patients receiving lobectomy. However, for patients who cannot tolerate lobectomy, a sublobar resection (wedge resection or segmentectomy) may be considered. Given improved technology in detecting smaller tumors, two large randomized studies are evaluating sublobar resection versus lobectomy for patients with peripheral tumors smaller than 2 cm. VATS has become an acceptable and reasonable alternative to standard thoracotomy, if there are no anatomic or surgical contraindications, based on large case series showing equivalent long-term outcomes and less short-term morbidity. Radiation therapy following surgery is considered for margin-positive disease or pathologic mediastinal lymph node involvement.
Patients with clinical stage I primary NSCLC, who are not candidates for surgery because of significant comorbidity or other surgical contraindication, are candidates for stereotactic body radiotherapy. Stereotactic body radiotherapy, which is composed of multiple non-parallel radiation beams that converge, allows the delivery of a relatively large dose of radiation to a small, well-defined target. For clinical stage I NSCLC, 3-year local control rates with stereotactic body radiotherapy exceed 90%, and large meta-analyses of nonrandomized data have shown 2-year survival of 70% and 5-year survival of 40%. Patients with locally advanced disease (stages IIIA and IIIB) who are not surgical candidates have improved survival when treated with concurrent chemotherapy and radiation therapy compared with no therapy, radiation alone, or even sequential chemotherapy and radiation.
Neoadjuvant chemotherapy consists of giving antineoplastic drugs in advance of surgery or radiation therapy. There is no consensus on the impact of neoadjuvant therapy on survival in stage I/II NSCLC, and such therapy is not recommended outside of ongoing clinical trials. Neoadjuvant therapy is more widely used in selected patients with stage IIIA or select stage IIIB disease. Some studies suggest a survival advantage. This remains an area of active research.
Adjuvant chemotherapy consists of administering antineoplastic drugs following surgery or radiation therapy. Cisplatin-containing regimens have been shown to confer an overall survival benefit in at least stage II disease and a subset of stage IB disease where primary tumor size exceeds 4 cm. The Lung Adjuvant Cisplatin Evaluation Collaborative Group, a meta-analysis of the five largest cisplatin-based adjuvant trials, reported a 5% absolute benefit in 5-year overall survival with a cisplatin-containing doublet regimen following surgery (P = 0.005) in patients with at least stage II disease. For patients with poor performance status (Eastern Cooperative Oncology Group Score of 2 or more), there is no evidence of survival benefit for adjuvant chemotherapy; rather, it may be detrimental.
For stage IIIB and stage IV NSCLC, options for therapy include targeted therapy, cytotoxic chemotherapy, and immunotherapy (checkpoint inhibitors) (Tables 39–2 and 39–3). The approach to therapy is individualized based on molecular profiling and PD-L1 testing. Molecular profiling is offered as next-generation sequencing multi-gene assays. The key driver mutations in lung cancer currently include EGFR, ALK, BRAF, and ROS1, but only a minority of all lung cancer cases harbor these mutations. K-ras mutation is more commonly found among smokers but has not been targeted effectively. These mutations (EGFR, ALK, ROS-1, BRAF, and K-ras) are mutually exclusive. Difficulties in testing may arise when only small fine-needle aspirate biopsies are obtained; to have sufficient tissue for analysis, it is recommended that clinicians obtain core biopsies. PD-L1 expression is a flawed but actively used biomarker to assess possible response to checkpoint inhibitor therapy (specifically, programmed death-1 [PD-1] inhibitors).
Targeted therapy has played a pivotal role in advanced NSCLC (Tables 39–2 and 39–3). Activating EGFR mutations are found in approximately 10–20% of the white population and 30–48% of the Asian population and are usually found among nonsmokers to light smokers, females, and persons with nonsquamous histologies (particularly adenocarcinomas). For patients with EGFR mutations, an EGFR tyrosine kinase inhibitor (osimertinib, erlotinib, gefitinib, afatinib, or dacomitinib) rather than platinum-based chemotherapy is the first-line treatment. Response rates with EGFR tyrosine kinase inhibitors in patients with EGFR mutation are at least 70%, and median overall survival is estimated to be 21–33 months. Recent phase III data show that osimertinib (third-generation irreversible EGFR tyrosine kinase inhibitor) leads to a longer duration of response, longer progression-free survival, and lower rates of severe adverse events compared to earlier generation EGFR tyrosine kinase inhibitors. Osimertinib is FDA approved as first-line treatment of EGFR-mutated lung cancers. Eventual resistance to therapy develops for patients taking osimertinib, and options for second-line therapy include platinum-based chemotherapy and/or immunotherapy.
Approximately 5% of all patients with NSCLC carry translocations of ALK resulting in novel fusion gene products with oncogenic activity. This is usually found in a comparatively younger population, with adenocarcinoma histology, and nonsmoking to light-smoking history. For patients with ALK-rearranged lung cancers, ALK tyrosine kinase inhibitors (alectinib, ceritinib, crizotinib, brigatinib, and lorlatinib) are recommended therapeutic agents. Recent randomized trials have shown that alectinib compared to crizotinib in first-line treatment of ALK-rearranged lung cancers has superior response rates (83% vs 75%), longer progression-free survival, and longer time to CNS progression. Alectinib is now recommended as the first-line agent in ALK-rearranged lung cancers. For patients who have developed resistance to either first- or second-generation ALK inhibitors, lorlatinib (a third generation ALK and ROS1 tyrosine kinase inhibitor) has shown a response rate of 47%. Approximately 1–2% of NSCLC harbor ROS1 rearrangements and are usually found among nonsmokers or light smokers with lung adenocarcinomas. ROS1-rearranged lung cancers also respond to crizotinib (ALK, cMET, and ROS1 tyrosine kinase inhibitor) with response rates over 70%. BRAF mutations have been found in 2% of NSCLC patients and often in smokers. The combination of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) has shown response rates of over 60% in patients with BRAF V600E mutations. Finally, K-ras mutations are found among 25% of patients with adenocarcinomas, are associated with smoking, and indicate a poor prognosis. Early clinical trials are underway evaluating the role of novel K-ras inhibitor, AMG 510, in treating K-ras G12C mutated lung cancers. Ongoing research seeks to define the role of these targeted agents in early stage and locally advanced lung cancers, mechanisms of resistance, and identification of new novel mutations, especially in squamous cell carcinomas where no approved targeted therapy exists.
Immune checkpoint inhibition using PD-1 or PD-L1 inhibitors (nivolumab, pembrolizumab, atezolizumab, and durvalumab) has an important role in the treatment of NSCLC (Tables 39–2 and 39–3). Checkpoint inhibitors release T cells from the inhibitory signals they receive from tumor cells via the PD-1 pathway, restoring antitumor immunity. For patients with tumors staining greater than 50% for PDL-1, pembrolizumab outperforms first-line platinum-based chemotherapy, with response rates of 45% vs 28% and median progression-free survival of 10 months vs 6 months. Phase III trials have shown improved survival outcomes with adding pembrolizumab to platinum-doublet chemotherapy as first-line therapy of patients with advanced NSCLC regardless of PD-L1 status. If patients received chemotherapy alone as first-line treatment, PD-1 inhibitors are recommended as second-line treatment of NSCLC, regardless of PD-L1 staining intensity. This treatment strategy yields an approximately 20% response rate, a durable response, and superior overall and progression-free survival rates compared to standard second-line chemotherapy. Combined checkpoint inhibition with nivolumab (PD-1 inhibitor) and ipilimumab (monoclonal CTLA4 antibody) has also shown improved response rates and progression-free survival compared with chemotherapy in patients with metastatic NSCLC. However, significant side effects and toxicity have been reported with checkpoint inhibitors, especially autoimmune manifestations such as hepatitis, thyroiditis, hypophysitis, colitis, pneumonitis, and type 1 diabetes mellitus. Recently, a randomized phase III trial has shown improved survival outcomes by adding durvalumab as consolidation therapy post-definitive chemoradiation for stage III NSCLCs. Further research is exploring the potential role of PD-1 or PD-L1 inhibitors in other indications, such as adjuvant therapy post-surgery.
If no targetable mutations are found and there is inadequate PD-L1 expression on tumor cells, patients are either offered combination immunotherapy with cytotoxic chemotherapy or cytotoxic chemotherapy alone (Table 39–2). Although not curative, chemotherapy has been shown in multiple clinical trials to provide a modest increase in overall survival in patients with stage IIIB and stage IV NSCLC compared with supportive care alone, with the median survival increased from 5 months to a range of 8–12 months and 1-year survival rate of 30–40%. Palliative chemotherapy also leads to improved quality of life and symptom control, with first-line therapy involving a platinum-based regimen. Platinum-based doublet regimens consist of cisplatin or carboplatin (agents that bind DNA to form adducts that inhibit their synthesis and function) combined with another agent, such as pemetrexed, gemcitabine, taxane, or vinorelbine. The choice of chemotherapeutic agent should be tailored to histologic subtype in NSCLC. For good performance status patients with nonsquamous histologies, bevacizumab (a monoclonal antibody to vascular endothelial growth factor [VEGF]) can be added to a traditional platinum doublet regimen with further modest increase in survival benefit. Maintenance chemotherapy, that is, ongoing chemotherapy after an induction period of 4–6 cycles, has also been shown to improve overall survival.
B. Small Cell Lung Carcinoma
Response rates of SCLC to cisplatin and etoposide (Table 39–2) are excellent with 80–90% response in limited-stage disease (50–60% complete response), and 60–80% response in extensive-stage disease (15–20% complete response). However, remissions tend to be short-lived with a median duration of 6–8 months. Once the disease has recurred, median survival is 3–4 months. Overall 2-year survival is 20–40% in limited-stage disease and 5% in extensive-stage disease (Table 39–5). Modest improvement in survival has been achieved with the addition of a checkpoint inhibitor (atezolizumab) to carboplatin and etoposide therapy in extensive stage disease. Thoracic radiation therapy improves survival in patients with limited SCLC and is given concurrently with chemotherapy. Consolidative thoracic radiation therapy may be indicated for patients with extensive disease who have a significant response to chemotherapy and remain free of brain metastases. There is a high rate of brain metastasis in patients with SCLC, even following a good response to chemotherapy. Prophylactic cranial irradiation has been shown to decrease the incidence of central nervous system disease and to improve survival in patients with limited-stage disease who respond to chemotherapy and in a subset of patients with extensive-stage disease who have had an excellent response to chemotherapy.
Table 39–5.Median survival for small cell lung carcinoma following treatment. ||Download (.pdf) Table 39–5. Median survival for small cell lung carcinoma following treatment.
Mean 2-Year Survival
Occasionally, very early limited-stage disease (T1N0M0) may be detected on initial imaging. It may also be identified after a peripheral nodule proves to be SCLC on resection. These patients are recommended to receive adjuvant chemotherapy following surgery given the high risk of micrometastases in SCLC. Five-year survival following resection and adjuvant chemotherapy for stage I SCLC can reach up to 50%.
Photoresection with the Nd:YAG laser is sometimes performed on central tumors to relieve endobronchial obstruction, improve dyspnea, and control hemoptysis. External beam radiation therapy is also used to control dyspnea, hemoptysis, endobronchial obstruction, pain from bony metastases, obstruction from superior vena cava syndrome, and symptomatic brain metastases. Resection of a solitary brain metastasis improves quality of life and survival when combined with radiation therapy if there is no evidence of other metastatic disease. Stereotactic radiation therapy is offered for limited brain metastases. Repeated thoracenteses, pleurodesis, or pleurex catheter tube placement are key interventions for palliation of symptomatic malignant pleural effusions. Pain is very common in advanced disease. As patients approach the end of life, meticulous efforts at pain control are essential (see Chapter 5). In addition to standard oncologic care, early referral to a palliative care specialist is recommended in advanced disease to aid in symptom management and such palliative care can modestly improve survival.