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Stages I and II Disease
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Surgery is standard treatment for stages I and II NSCLC (Figs. 18-18 and 18-19).
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The extent of lung resection will be dictated by the size and location of the tumor. The entire tumor must be removed, with margins negative for cancer. Wedge resection and segmentectomy are associated with higher rates of local recurrence than lobectomy and pneumonectomy and are not considered standard of care, although they may be an option for patients who cannot tolerate a larger surgery due to poor pulmonary function (35). All patients should also undergo complete ipsilateral mediastinal lymph node dissection or systematic mediastinal sampling for accurate staging (36).
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Any patient who is being considered for surgery must undergo pulmonary function tests to assess the ability to withstand pulmonary resection. Split-lung function studies can further help to predict lung function after the planned resection. There is no single accepted value, criterion, or cutoff for pulmonary resection. Published criteria that have been shown to predict high risk for lung resection include estimated posttreatment forced vital capacity <2 L, forced expiratory volume in 1 second <1 L, and diffusing capacity of the lungs for carbon dioxide <40% to 60% (37).
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For patients with early-stage lung cancer who cannot undergo surgery because of poor pulmonary reserve or medical comorbidities, stereotactic radiosurgery is a feasible option with local control rates of 90% and cancer-specific survival of 88% at 3 years (38).
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There is controversy regarding whether stereotactic radiosurgery should be considered in patients who are candidates for surgery and who have small primary tumors and no lymph node involvement. Retrospective series suggest that outcomes with radiation may be similar to those of surgery (38). Surgery, however, remains the standard of care for patients who can tolerate it.
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Adjuvant Chemotherapy
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Even after complete resection, rates of recurrence of NSCLC are high, prompting the study of adjuvant chemotherapy in this disease. The potential benefit of adjuvant chemotherapy is the eradication of micrometastatic disease before it becomes clinically evident, thus potentially increasing cure rates. For patients with completely resected stage II or III NSCLC, multiple meta-analyses demonstrate that adjuvant platinum-based chemotherapy is associated with an absolute benefit in 5-year survival of about 5% (39) and should be offered to all patients with good performance status (Table 18-12) (40,41,42,43,44). For patients with no lymph node involvement and a primary tumor smaller than 4 cm, adjuvant chemotherapy is not recommended. For node-negative tumors larger than 4 cm, the Cancer and Leukemia Group B 9633 trial suggested a benefit of adjuvant platinum-based chemotherapy, and it should be considered (40) (see Table 18-12).
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Cisplatin-vinorelbine is the most studied regimen for adjuvant chemotherapy; in practice, other cisplatin-based doublets are frequently used. Acceptable second agents include pemetrexed (for nonsquamous NSCLC), docetaxel, etoposide, and gemcitabine. Cisplatin is preferred over carboplatin, but if cisplatin is not feasible, carboplatin/paclitaxel is an appropriate alternative (40). There is no evidence that targeted agents such as bevacizumab, erlotinib, and crizotinib are effective in the adjuvant setting, although the National Cancer Institute ALCHEMIST trial will assess the benefit for specific molecular subsets of patients.
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Neoadjuvant chemotherapy offers several real and theoretical advantages over postoperative therapy: better patient compliance, improved tumor resectability, earlier treatment of micrometastatic disease, and earlier assessment of clinical and pathologic response. There has been one randomized trial and one meta-analysis (45) that suggest the equivalence of the neoadjuvant and adjuvant approaches. Adjuvant treatment is the standard of care, but neoadjuvant chemotherapy could be considered in special situations, such as for stage III disease when response to chemotherapy may help to determine whether a patient should undergo surgery or chemoradiation.
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Adjuvant radiation or chemoradiation for resected stage I and II NSCLC has been shown to be detrimental and should not be recommended (46).
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Patients with stage III disease have better outcomes with multimodality rather than single-modality therapy, and their care should be managed by a multidisciplinary team. For patients with stage IIIB disease, chemoradiation represents the standard of care. Chemoradiation is often used for patients with stage IIIA disease as well, but surgery with adjuvant treatment can be considered for carefully selected patients.
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In a randomized trial of chemoradiation alone versus chemoradiation followed by resection, the patients who benefited from the surgical approach were those with stage IIIA disease who had limited involvement of mediastinal lymph nodes and who underwent lobectomy (as opposed to pneumectomy) (47). Neoadjuvant chemoradiation followed by surgery has been compared to neoadjuvant chemotherapy followed by surgery and adjuvant radiation (48) and was associated with more toxicity with no survival benefit. At MDACC, we consider surgical treatment in patients with stage IIIA disease with good performance status and without multistation mediastinal adenopathy. These patients are typically treated with neoadjuvant chemotherapy followed by consideration of surgery. Adjuvant radiation therapy is typically given if there is evidence of mediastinal node involvement based on assessment of surgical pathology (Fig. 18-20).
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Patients with stage IIIA disease and extensive mediastinal involvement or IIIB disease should be treated with concurrent chemoradiation. When compared with sequential radiotherapy and chemotherapy, this approach is associated with higher survival rates (23.8% vs 18.1% at 3 years; hazard ratio [HR], 0.84; P = .004) but increased toxicity (acute esophageal toxicity, 18% vs 4%; relative risk [RR], 4.9; P = .001) (49).
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Standard radiotherapy for stage III NSCLC consists of radiation given once daily for 6 weeks (30 fractions) to a total dose of 60 Gy. All attempts to increase efficacy through hyperfractionation, acceleration, or increased radiation dose have failed (50). In the recent Radiation Therapy Oncology Group 0617 trial, patients receiving high-dose radiation (74 Gy) had higher rates of locoregional failure (44% vs 35.3%; P = .04) and worse median survival (19.5 vs 28.7 months; P = .0007) than those receiving standard-dose radiation (60 Gy) (51). Proton therapy is a newer technique that is able to deliver a higher dose to the tumor while delivering lower doses to normal surrounding tissue; it is currently being compared to standard radiation in a randomized phase III trial (NCT00915005).
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Multiple concurrent chemotherapy regimens have been tested against radiation alone with proven benefit (52); however, these regimens have not been directly compared to each other, and multiple regimens are considered acceptable (Table 18-13). At MDACC, many physicians favor carboplatin and paclitaxel because retrospective data suggest that this regimen is less toxic than cisplatin and etoposide (53).
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The use of consolidation docetaxel after concurrent chemoradiation with cisplatin and etoposide was detrimental in the phase III Hoosier Oncology Group LUN 01-24 trial (54). However, most studies with carboplatin/cisplatin and pemetrexed or carboplatin and paclitaxel included consolidation chemotherapy after radiation. It is reasonable to consider consolidation chemotherapy for patients who received those regimens and have a good performance status at the end of concurrent therapy.
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There are no definitive data on adjuvant anti-EGFR tyrosine kinase inhibitors (TKIs) in stage III NSCLC patients with activating EGFR mutations. In a population not selected for EGFR mutations, adjuvant gefitinib was detrimental (55). There is no proven benefit for any targeted therapies in combination with chemoradiation for locally advanced lung cancer, although this is an active area of investigation.
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Tumors in the lung apex invading apical structures, termed Pancoast tumors (Fig. 18-21), are challenging. Tumors that are N0 to N1 should undergo preoperative concurrent chemoradiation followed by resection. For these patients, 5-year disease-free survival rates are 40% to 50% (56). Patients with N2 to N3 disease should be treated with concurrent chemoradiation alone.
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Stage IV NSCLC remains an incurable disease, and management should include adequate palliation of symptoms. Patients with symptomatic brain or spinal cord metastases, hemoptysis, postobstructive pneumonia, or painful bone metastases should receive radiotherapy before any consideration for systemic therapy. Early referral to specialized palliative care services has also been shown to improve overall survival (57).
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Decisions about systemic therapy demand the classification into SCC versus nonsquamous carcinoma and the testing of adenocarcinoma cases for actionable alterations (eg, EGFR mutations, ALK and ROS1 rearrangements). The most recent guidelines (58) recommend that all adenocarcinomas, mixed adenosquamous carcinomas, and NSCLCs not otherwise specified should undergo evaluation for EGFR mutations using polymerase chain reaction–based tests and testing for ALK and ROS1 translocations using fluorescent in situ hybridization. Often, in practice, more complete molecular profiling is being performed, which also includes testing for less common alterations such as BRAF and HER2 mutations and RET fusions. Pure SCC with no immunohistochemistry markers of adenocarcinoma should not undergo molecular testing. Because of the importance of molecular testing, attempts should be made to obtain core biopsies rather than fine-needle aspirations to ensure sufficient tissue for profiling.
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Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for EGFR Mutant Lung Adenocarcinoma
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Epidermal growth factor receptor (EGFR) TKIs should be considered first-line therapy in patients with metastatic lung adenocarcinoma with EGFR exon 19 deletion or L858R mutation. Exon 20 mutations (including T790M), which are found in 5% of cases at diagnosis, have an intrinsic resistance to EGFR-TKIs (27) and should be treated with standard chemotherapy.
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The EGFR-TKIs erlotinib, afatinib, and gefitinib have been tested against standard chemotherapy as first-line agents in patients with NSCLC with EGFR-activating mutations and showed improvement in response rates (70% vs 33%, P < .001), progression-free survival (PFS) (9.5 to 13.1 months vs 4.1 to 6.3 months, P < .0001), and quality of life (59,60,61). No benefit in overall survival (OS) has been detected because most trials allowed for cross-over after progression (Table 18-14) (59,60,61,62,63,64,65). Gefitinib is not available in the United States, so either erlotinib or afatinib can be used in the frontline setting. There are no head-to-head data comparing erlotinib to afatinib, and afatinib has higher reported rates of toxicity. There is some evidence that combining EGFR-TKIs with the anti–vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab improves response rates and PFS (66), but benefits in OS have not been confirmed.
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Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors
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Patients with activating EGFR mutations who progress on EGFR-TKIs and those with unknown mutation status who have a prolonged response to EGFR TKIs (>6 months) and then progress are classified as having acquired resistance to EGFR-TKIs. For these patients, a postprogression biopsy is recommended to identify the mechanisms of resistance (67,68) (Fig. 18-22).
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In about half of cases, the mechanism of resistance is the development of an acquired exon 20 T790M mutation, which occurs at the binding site of the TKI to EGFR, displacing the TKI. The growth of those tumors still shows EGFR dependence, and multiple trials are currently evaluating the effects of third-generation TKIs (eg, AZD9291 and CO-1686) with specific affinity for EGFR with T790M mutation. Early data look promising, and these agents may receive regulatory approval in the near future. There are also phase I/II data on using the combination of afatinib with the anti-EGFR monoclonal antibody cetuximab in patients with acquired EGFR resistance (response rate, 29%; PFS, 4.7 months) (69). Interestingly, efficacy was similar in patients with and without T790M mutations. Currently, however, there are no approved targeted agents for patients with resistance to first-line TKIs.
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About 5% of patients experience small cell transformation. These patients should be treated similarly to de novo SCLC with combination chemotherapy such as platinum-etoposide (see Chapter 17 on SCLC for further details on SCLC chemotherapy regimens) (67).
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Because erlotinib has poor penetration through the blood-brain barrier, patients with controlled extracranial disease who are progressing in the CNS may benefit from pulsatile high-dose erlotinib (1,500 mg once a week), with response rates in the CNS of 67% and median time to CNS progression of 2.7 months (70). This approach is also being further studied in clinical trials. Another option is treating the brain metastases with radiation and continuing with erlotinib (71).
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Outside of clinical trials, patients with resistance to frontline TKIs should receive standard chemotherapy (see below). Postprogression continuation of EGFR-TKIs in combination with chemotherapy has recently been addressed with two clinical trials. The data demonstrate that despite increases in response rates compared to chemotherapy alone, PFS and OS are not improved (72).
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ALK Inhibitors for Patients With Adenocarcinomas With ALK Translocations or ROS1 Fusions
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Approximately 5% of patients with adenocarcinoma have tumors harboring an ALK fusion, and another 1% to 2% of patients have a ROS1 fusion. For patients with an ALK translocation, treatment with crizotinib is associated with response rates greater than 60% and median PFS around 8 months (62). Crizotinib is similarly effective in patients with ROS1 translocations, with response rates over 70% and median PFS over 19 months (65). Crizotinib is the standard first-line therapy in patients with advanced lung adenocarcinoma with EML4-ALK translocations or ROS1 fusions (see Table 18-14).
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The mechanisms of resistance to crizotinib therapy have been studied. About 46% of patients develop further alterations in the ALK gene (28% secondary ALK mutations, 18% ALK copy number gains), 8% develop EGFR mutations, and 18% develop KRAS mutations (73). The most common resistance mutations are L1196M and G1269A, which occur at the crizotinib binding site. Another proposed mechanism of resistance is the overexpression of insulin-like growth factor receptor 1 (IGF-1), which activates the same downstream pathways as ALK.
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Regardless of the mechanism of resistance, patients with acquired resistance to crizotinib should receive second-line treatment with one of the second-generation ALK inhibitors. Ceritinib has shown promising results in a large phase I trial and is US Food and Drug Administration (FDA) approved for ALK-positive patients following progression on crizotinib (63). Other second-generation ALK inhibitors, including alectinib, AP26113, and X-396, are currently in clinical development (see Table 18-14).
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Frontline Chemotherapy for Advanced Non–Small Cell Lung Cancer
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Most patients with lung cancer do not have a tumor that is targetable with an approved therapy. For these patients, as well as for patients with EGFR mutation or ALK or ROS1 fusions progressing on targeted therapies, cytotoxic chemotherapy represents the standard of care.
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When compared to best supportive care, chemotherapy is associated with a modest improvement in median OS (1.5 months) and significant gains in symptom control (74). Multiple platinum-based doublets are equally effective with response rates around 18% to 35%, PFS of 3 to 6 months, and OS of 8 to 12 months (75,77,78,79) (Table 18-15). Acceptable agents to combine with platinum include paclitaxel (75), docetaxel (75), pemetrexed (76,77) (nonsquamous only), gemcitabine (75), and nab-paclitaxel (78). One trial showed that cisplatin-pemetrexed is superior to cisplatin-gemcitabine in patients with adenocarcinoma but inferior in patients with SCC (76,77). Because this combination is relatively well tolerated and has a convenient once every 3 weeks dosing schedule, it is often used as first-line therapy in patients with adenocarcinoma.
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In the past, trials suggested that cisplatin was associated with better response rates and PFS than carboplatin, but a meta-analysis focusing only on modern regimens (docetaxel, paclitaxel, vinorelbine, or gemcitabine combined with platinum) (80) showed that carboplatin and cisplatin lead to similar outcomes. The toxicity profile is different, and cisplatin has a higher risk for nausea, whereas carboplatin has higher rates of myelosuppression.
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The addition of the VEGF monoclonal antibody bevacizumab to carboplatin/paclitaxel can be considered in patients with adenocarcinomas. The phase III Eastern Cooperative Oncology Group (ECOG) 4599 trial (79) randomized patients with nonsquamous NSCLC to carboplatin and paclitaxel with or without bevacizumab. The bevacizumab-containing arm had better response rates (35% vs 15%, P < .001), PFS (6.2 vs 4.5 months, P < .001), and OS (12.3 vs 10.3 months, P = .003), although there were higher rates of adverse events, including a higher risk of severe bleeding (4.4% vs 0.7%, P < .001). Patients with squamous histology, hemoptysis, or uncontrolled hypertension and those older than 70 are at higher risk for bleeding with bevacizumab and are not candidates for this therapy.
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Maintenance Chemotherapy
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For patients who do not progress after four to six cycles of therapy with a platinum doublet, multiple trials have studied maintenance therapy—either continuation maintenance (continuing the same nonplatinum drug) or switch maintenance (initiating a non-cross-resistant nonplatinum drug) (Table 18-16) (81,82,83,84,85,86,87).
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Patients receiving either pemetrexed or bevacizumab as part of their initial therapy should continue these drugs as long as tolerated or until progression (79,85,86). For patients who are treated with other frontline regimens, maintenance therapy is more controversial. Switch maintenance to either pemetrexed (for nonsquamous NSCLC) (82) or docetaxel (81) is associated with benefits in PFS, although effects on OS are unclear, particularly for patients who go on to receive second-line therapy. Maintenance pemetrexed in patients with SCC has been shown to be associated with shorter PFS (82) than observation alone; based on these data and the other data described earlier, pemetrexed should not be used for patients with NSCLC with predominantly squamous histology.
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Chemotherapy for Patients With Platinum-Refractory Disease
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Patients with disease progression after platinum-based therapy who maintain good performance status are candidates for second-line therapy. The agents with proven efficacy in this setting are single-agent docetaxel, pemetrexed (in nonsquamous NSCLC only), and ramucirumab in combination with docetaxel (Table 18-17) (77,88,89,90,91,92,93,94,95). Second-line pemetrexed is equivalent to docetaxel in nonsquamous histologies (response rate, 12.8% vs 9.9%; OS, 9 vs 9.2 months) but inferior in squamous NSCLC (response rate, 2.8% vs 8.1%; OS, 6.2 vs 7.4 months; P = .018).
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Reexposure to platinum in second-line therapy increases response rates, but not PFS or OS, even in patients with long (>6 months) platinum-free intervals (91) and is not frequently used. The only combination therapy approved in the second-line setting is docetaxel with the anti-VEGF receptor 2 (anti-VEGFR2) monoclonal antibody ramucirumab (92). In the pivotal REVEL trial comparing docetaxel alone to docetaxel plus ramucirumab in patients with NSCLC of any histology, the combination arm had better PFS (4.5 vs 3 months, P < .0001) and OS (10.5 vs 9.1 months, P = .023) with no increased risk of severe bleeding. It is important to highlight that only 14% of patients enrolled in REVEL had received prior bevacizumab, making it difficult to draw conclusions about this group. Also, unlike the phase III bevacizumab trials that excluded patients with SCC, 25% of patients on this trial had squamous histology, and there was no increased risk of bleeding seen in this group.
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For patients with wild-type EGFR, docetaxel and pemetrexed appear to be better second-line options than erlotinib (93,95), although erlotinib remains an FDA-approved option for third-line therapy (94).
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Treatment of Stage IV Non–Small Cell Lung Cancer in the Elderly
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Treatment of advanced NSCLC in the elderly has been addressed in several prospective studies and retrospective analyses, and the International Society of Geriatric Oncology (SIOG) has issued clear guidelines (96). Basically, patients older than age 70 years should undergo functional evaluation, and those with good functionality should receive standard therapy.
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For lung adenocarcinomas with actionable mutations, TKIs should be recommended. For patients without actionable mutations, platinum-based doublets should be offered. In the IFCT-0501 trial (97), patients older than age 70 were randomized to carboplatin-paclitaxel or single-agent therapy with vinorelbine or gemcitabine. The combination arm had a significant improvement in OS (10.3 vs 6.2 months, P < .0001) and better pain control rates with a small increase in the rates of toxic death (4.4% vs 1.3%). Based on the subgroup analysis from ECOG 4599 (98) and on other trials, bevacizumab should not be added to chemotherapy in elderly patients because of lack of benefit and increased risk of severe side effects.
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Immunotherapy in Advanced Non–Small Cell Lung Cancer
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Immunotherapy has recently achieved significant outcomes in the treatment of metastatic melanoma, leading to the approval of immune checkpoint inhibitors such as anti-PD-1/PD-L1 and anti-CTLA4 antibodies (see chapter on cancer immunotherapy). Lung cancers are among the malignancies with the highest mutation burden, averaging 360 exonic mutations per sample (23). Many of those mutations generate neoantigens potentially able to stimulate effector CD8+ T cells. It has also been shown that NSCLC with high tumor-infiltrating lymphocytes have better outcomes after resection and in the metastatic setting (99), suggesting lung cancers as good candidates for the investigational use of immunotherapies.
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Previous trials focused on cancer vaccines in NSCLC, which were shown to induce tumor-specific immune responses but failed to improve survival (100). The development of immune checkpoint inhibitors has renewed the interest in immunotherapy approaches for NSCLC (Table 18-18) (101,102,103,104,105,106).
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The CTLA4 receptor on T cells interacts with the B7-1 and B7-2 proteins on antigen-presenting cells and downregulates the T-cell response to tumor-related antigens. There are two anti-CTLA4 antibodies currently approved for the treatment of melanoma: ipilimumab and tremelimumab. In a randomized phase II trial for NSCLC patients (101), the addition of ipilimumab during cycles 3 to 6 of first-line chemotherapy with carboplatin and paclitaxel was associated with better response rates and a nonsignificant increase in OS. There are multiple trials under way to investigate how best to use these agents in patients with metastatic disease (eg, alone or in combination, timing in combinations, incorporation of molecular markers for selection), such as the randomized trial with carboplatin/paclitaxel with or without ipilimumab for patients with squamous histology (NCT01285609).
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PD-1 is another receptor expressed on T cells that, upon interaction with its ligand, PD-L1, suppresses immune cell activation. Expression of PD-L1 on antigen-presenting cells and on tumor cells is believed to be a key player in local tumor microenvironment-mediated immunosuppression. Approximately 35% to 50% of stage IV NSCLC patients have moderate to high staining of PD-1 or PD-L1 depending on the methodology for staining and scoring.
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Two anti-PD-1 antibodies have been studied in phase I and II trials of NSCLC: nivolumab and pembrolizumab (see Table 18-18). In general, the response rates have been 15% to 25% both in the first- and second-line settings, and the OS has been around 8 to 10 months, with no difference between adenocarcinoma and SCC. However, some responders have prolonged disease control, sometimes for more than 12 months. No predictor of response has been validated yet, but it appears that tumors with higher expression of PD-L1 (105) and those with PD-L1–positive tumor-infiltrating lymphocytes (106) have better outcomes when treated with anti-PD-1/PD-L1 agents. There are also data emerging from several groups on regulation of the dynamic PD-L1 expression of tumor cells, including the effect of epithelial-to-mesenchymal transition to drive CD8+ T-cell suppression through PD-L1 activation (107).
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The use of anti-PD-1/anti-PD-L1 therapy currently remains investigational, but the pending results of phase II and III trials of pembrolizumab and nivolumab in metastatic NSCLC could substantially change the landscape of treatments options in the near future.
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Other Therapies for Advanced Disease and Management of Oligometastatic Disease
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Radiotherapy and surgery may be helpful in managing selected patients with stage IV NSCLC. Radiotherapy can be used to palliate pain or to manage hemoptysis and obstructive symptoms in large primary tumors.
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In patients with solitary brain metastasis as their only site of metastatic disease, resection or stereotactic radiation of the brain lesion followed by definitive therapy to the primary tumor (resection or radiation) is associated with significant improvement in median OS (26 months vs 13 months in patients who do not undergo therapy to the primary tumor), and 5-year survival rates are 34% versus 0% (108).
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In patients with solitary adrenal metastasis, adrenalectomy associated with definitive therapy to the primary tumor also has good outcomes, with a median OS of 26 months and 5-year survival rates of 30%, which has been consistent in multiple studies (109). Patients who develop isolated adrenal metastasis more than 6 months after the resection of the primary tumor are the ones with the most benefit.
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Patients with oligometastatic disease (one to five lesions) should undergo extensive workup including PET-CT scan and brain MRI. They can then be classified into three subgroups (110):
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Low risk: Development of oligometastatic disease more than 2 months after resection of the primary tumor (5-year OS, 47.8%).
Intermediate risk: Synchronous metastases (at presentation or within 2 months of the resection of the primary) and no lymph node involvement (N0) disease (5-year OS, 36.2%).
High risk: Synchronous metastases and N1/N2 disease (5-year OS, 13.8%).
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There is currently one randomized trial ongoing evaluating the effect of definitive treatment (surgery or radiation) for oligometastatic disease (NCT01725165). However, observational studies have shown that, in patients who received two cycles of systemic therapy and did not have progression, definitive therapy to oligometastasis was associated with improvements in OS (27 vs 13 months; HR, 0.37; 95% confidence interval [CI], 0.2-0.7; P < .01) (111). There are also data suggesting that, for patients with oligometastatic disease receiving chemotherapy, radiation therapy to the primary tumor is associated with improved OS (HR, 0.65; 95% CI, 0.43-0.93; P = .019) (112).