Non-Small Cell Lung Cancer Treatment & Management

Updated: Aug 17, 2017
  • Author: Winston W Tan, MD, FACP; Chief Editor: Nagla Abdel Karim, MD, PhD  more...
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Treatment

Approach Considerations

Surgery is the treatment of choice for patients with non–small cell lung cancer (NSCLC) stages I through IIIA. [14] In addition, patients with resected lung cancer have a high risk of relapse and are treated with adjuvant chemotherapy. [74] Patients with stage IIIB and IV NSCLC are usually offered chemotherapy with the option of surgery. Radiation is a reasonable option for treatment in patients who are not candidates for surgery; the role of adjuvant radiation therapy after resection of the primary tumor remains controversial.

See the table below, as well as Non-Small Cell Lung Cancer Treatment Protocols.

Treatment recommendations and future research dire Treatment recommendations and future research directions in the management of non–small cell lung cancer.

Because most NSCLC cannot be cured with currently available therapeutic modalities, the appropriate application of skilled palliative care is an important part of treatment. Increasing evidence supports offering concurrent palliative care and standard oncologic care at the initial diagnosis of advanced NSCLC. [75]

For example, a clinical trial found that patients with metastatic NSCLC randomized to early palliative care had a better quality of life and, surprisingly, longer median survival than those randomized to standard oncologic care alone. The palliative care group also had less depressive symptoms, and fewer patients in this group received aggressive end-of-life care. [76]

Emergency Treatment

All patients thought to have lung cancer should be encouraged to obtain follow-up care with their primary care physician. In almost all cases, document the possible diagnosis and discuss it with the patient. Definitive treatment of the underlying cancer is not the purview of the emergency department (ED).

Emergency treatment is based on symptoms. In cases of upper airway obstruction, admit the patient to the intensive care unit (ICU), prepare for intubation and/or cricothyrotomy, and obtain otolaryngologic and/or surgical consultation for fiberoptic laryngoscopy or intraoperative tracheostomy.

If hemoptysis is noted, administer supplemental oxygen and perform suctioning. If a threat of imminent demise exists, consider placing a double-lumen endotracheal tube. Position the patient with the bleeding hemithorax in a dependent position. Perform arterial blood gas (ABG) and complete blood count (CBC) (type and crossmatching) coagulation studies if the bleeding is more than trivial. A pulmonologist may have to perform fiberoptic bronchoscopy. Admit patients, except those with the most minor bleeding, to the ICU.

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Surgical Treatment

Surgical resection remains the mainstay of treatment for all patients with stage I and II NSCLC—that is, those patients with no evidence of mediastinal disease or invasion of local organs. Lobectomy is the procedure of choice. Outcomes are better when the procedure is performed by a surgeon with specialty training, or is done in a higher-volume center or in a teaching facility. [8]

A study patients who underwent planned resection after an unexpected finding of N2 disease at the time of thoracoscopy or thoracotomy found that proceeding with lobectomy did not appear to compromise outcomes if adjuvant chemotherapy with or without radiation therapy was administered following surgery. [77]

The role of surgery for stage III disease is controversial. (See Stage-Based Management.) Patients with completely resectable primary tumors (ie, T4 N0) have a much better prognosis than those with spread to ipsilateral mediastinal or subcarinal lymph nodes (ie, N2), signifying that spread beyond the primary tumor is associated with a poor prognosis. Patients with stage IIIB or IV tumors are almost never surgical candidates.

Preoperative evaluation

Preoperative evaluation should include a careful assessment of resectability, cardiopulmonary reserve, and perioperative risk. High-resolution computed tomography (CT) and positron emission tomography (PET) scanning are helpful for preoperative planning in early-stage lung cancer. [78]

As a general guideline, most patients with a preoperative forced expiratory volume in one second (FEV1) of greater than 2.5 L are able to tolerate pneumonectomy. With an FEV1 of 1.1-2.4 L, a lobectomy is possible. Patients with an FEV1 of less than 1 L are not considered candidates for surgery. These factors are further modified by the presence of cardiac disease or other comorbid conditions.

Lobectomy and pneumonectomy

The standard surgical approach remains a lobectomy, which helps preserve pulmonary function while allowing a good resection. Hilar and other proximal tumors may require more extensive surgery, including a pneumonectomy, which carries significant operative mortality and long-term morbidity. In such patients, alternative approaches such as sleeve resection may be of value. [79]

Retrospective data from the Surveillance, Epidemiology, and End Results (SEER) database show that lobectomy and segmentectomy result in similar survival among patients with small lung cancers (< 1 cm). [80] This needs to be validated in a randomized phase III study.

Wedge resection/segmentectomy

Sublobar resections are used for patients with poor pulmonary reserve and are increasingly being used in conjunction with video-assisted thoracoscopic surgery (VATS). An older Lung Cancer Study Group trial, of stage IA cancers randomized to standard lobectomy versus sublobar resections, suggested a much higher local recurrence rate (75%), with a near-significant trend towards an increased cancer-specific mortality of 50%. [81]

However, a review of SEER data from 1988-2008 found that the survival benefit of lobectomy over sublobar resection for stage I NSCLCs ≤ 2 cm in size decreased over that time. By 2005-2008, both wedge resections and segmentectomies were equivalent to lobectomy. [82] A Cancer and Leukemia Group B (CALGB) phase III trial randomizing patients to lobectomy or limited resection for small peripheral IA lesions is ongoing, and should provide more clarity in this area. [83]

In patients older than 74 years with stage IA NSCLC, Okami et al found no significant difference in 5-year survival after sublobar resection versus standard lobectomy, although locoregional recurrence rates were higher after sublobar resection. [84] A study by Wolf et al showed that sublobar resection is a reasonable option for elderly patients with compromised cardiopulmonary status. [85]

Video-assisted thoracoscopic surgery

Video-assisted thoracoscopic surgery (VATS) is a minimally invasive surgical modality being used for both diagnostic and therapeutic lung cancer surgery. It offers low perioperative morbidity and mortality as well as decreased pain and hospitalization.

Recurrence rates and 5-year and long-term overall survival appear similar to those with traditional open thoracotomies. This approach is also better tolerated in older populations. [86] Finally, patients treated with VATS appear to have fewer delays and dose reductions in adjuvant chemotherapy. Practice guidelines suggest that VATS is feasible as long as adequate resection is possible. [87, 88]

Mediastinal lymphadenectomy

The role of routine mediastinal lymphadenectomy versus lymph node sampling remains controversial. The authors of a large randomized trial recommend that an adequate mediastinal lymphadenectomy should include exploration and removal of lymph nodes from stations 2R, 4R, 7, 8, and 9 for right-side cancers and stations 4L, 5, 6, 7, 8, and 9 for left-side cancers. [89]

For details on this procedure, see Mediastinal Lymphadenectomy.

Postoperative evaluation and complications

Residual pulmonary function after surgical resection is estimated using pulmonary function tests and radionuclide lung scans.

A study by Allen et al assessed curative-intent resections in a major US metropolitan area. The study found that most resections did not achieve good quality surgical resection (GQR) standards. [90] Although surgical sampling of mediastinal (level 2) lymph nodes was most lacking, evaluation of level 1 lymph nodes was also suboptimal. Further studies are indicated to assess surgical practices in order to achieve minimum standards for accurate staging, prognostication, and eligibility for clinical trials.

An understanding of post-surgical quality of life can help surgeons provide lung cancer patients with important information regarding postoperative outcomes. A study that measured health-related quality of life (HRQOL) in patients who underwent lung cancer surgery found that survivors exhibited clinically meaningful worse dyspnea, coughing, chest pain, and financial problems than the general population. [91]

The perioperative mortality rate is 6% for pneumonectomy, 3% for lobectomy, and 1% for segmentectomy. These rates reflect improvements in anesthesia and surgical techniques.

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Radiation Therapy

In the treatment of stage I and stage II NSCLC, radiation therapy alone is considered only when surgical resection is not possible because of limited pulmonary reserve or the presence of comorbidities. [2] Radiation is a reasonable option for lung cancer treatment in patients who are not candidates for surgery. [3] Radiation therapy alone as local therapy, in patients who are not surgical candidates, has been associated with 5-year cancer specific survival rates of 13-39% in early-stage NSCLC (ie, T1 and T2 disease). [92]

This inferior survival reflects the poor functional status of these patients, as well as the likelihood of these patients actually having a higher stage, given the known limitations of clinical staging. Survival appears to be enhanced by the use of hyperfractionation schedules, such as continuous hyperfractionated accelerated radiotherapy (CHART) at 1.5 Gy 3 times a day for 12 days, as opposed to conventional radiation therapy at 60 Gy in 30 daily fractions. Overall survival at 4 years was 18% vs 12%.

A study by Jeremić et al assessed independent prognosticators of outcome for hyperfractionated radiation therapy treatment. [93] The study found that female sex, lower Karnofsky performance score (KPS), less pronounced weight loss, squamous histology, lower stage, shorter interfraction interval, and treatment independently predicted better overall survival and progression-free survival. Age did not influence overall survival or progression-free survival.

A retrospective study of 722 patients with NSCLC undergoing radiotherapy who were taking beta blockers for another condition found that these patients had better overall survival, disease-free survival, and distant metastasis–free survival than patients not taking these drugs. Data showed a 22% improvement in overall survival in the beta-blocker group. However, there was no improvement in locoregional progression-free survival, which suggests that beta blockers affect the metastatic tumors rather than the primary tumor. [4, 5]

In a population-based study of 10,376 elderly patients with unresectable stage III NSCLC who were not candidates for chemotherapy, treatment with radiotherapy alone (specifically, complex radiotherapy) was associated with significantly improved survival. Median overall survival was found to be 9 months in the radiation-treated group (n=6468) and 7 months in the untreated patient group. [94, 95]

However, this was benefit was seen only in patients treated with complex radiotherapy, not in those who received intermediate complexity radiotherapy. In addition, patients treated with radiation were more likely to be hospitalized with pneumonitis or esophagitis.

Stereotactic body radiotherapy (SBRT) is another technique for nonoperative treatment of early-stage lung cancers. SBRT uses precise targeting of high-dose radiation to the tumor, typically in 1-2 fractions, while minimizing toxicity to normal tissues. Patients best suited for SBRT include those with a peripheral node-negative tumor that is less than 5 cm, in whom definitive surgery is contraindicated.

In a phase II study by Timmerman et al, use of SBRT in patients with inoperable NSCLC resulted in a 3-year survival rate of 55.8% (versus the 20%-35% seen with current management), high rates of local tumor control, and moderate treatment-related morbidity. [96] A large Japanese retrospective analysis showed that patients treated with SBRT at doses higher than 100 Gy had a local recurrence rate of 8.4%, and a 5-year overall survival of 70.8%. [97] Randomized studies of SBRT are being conducted by the Radiation Therapy Oncology Group (RTOG).

SBRT was associated with shorter overall survival but similar recurrence rates and cause-specific mortality in a nonrandomized study by Grills et al. The study compared outcomes in patients with stage T1-2N0M0 NSCLC who were ineligible for lobectomy and thus underwent either wedge resection or, if deemed medically inoperable, SBRT. [98]

Radiofrequency ablation (RFA) has also been used for inoperable patients who have peripheral tumors that are less than 3 cm in size, and occasionally in a palliative setting. In a single small nonrandomized prospective study, 2-year overall survival with stage I NSCLC was 75% (45-92%). This may be an option for patients in whom both surgery as well as traditional external beam radiation therapy may be contraindicated. [99]

Planning 4-dimensional computed tomography (4DCT) scans can be used to minimize target volumes for lung cancer radiotherapy, but 4DCT results may not be fully representative of patient movement during radiotherapy. Dutch investigators have reported that megavoltage cinema images can identify patients in whom planning 4DCT scans are not representative and thus could be helpful in the treatment of small lesions. [100]

Adjuvant radiation therapy

The role of adjuvant radiation therapy after resection of the primary tumor remains controversial. [101, 102] Radiation therapy reduces local failures in completely resected (stages II and IIIA) NSCLC but has not been shown to improve overall survival rates. In one study, 5-year overall survival was actually worse (30% vs 53%). A retrospective SEER analysis also showed that survival was lower for this population.

A single phase III study using small fractions, with 3D treatment planning, showed a 5-year survival benefit in the radiation treatment arm (67% vs 58%). [103] This finding has not been replicated; hence, at this time, postoperative radiation therapy for stage I and II lung cancer is reserved for cases with positive margins, until further trials are conducted with modern radiation therapy planning and delivery.

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Systemic Chemotherapy

Only 30-35% of patients with NSCLC present with sufficiently localized disease at diagnosis that curative surgical resection may be attempted (stages IA and IB, IIA and IIB, and IIIA). Furthermore, approximately 50% of patients who undergo surgical resection experience local or systemic relapse. Thus, approximately 80% of all patients with lung cancer are considered for chemotherapy at some point during the course of their illness.

At present, chemotherapy alone has no role in potentially curative therapy for NSCLC. Some trials have shown a survival benefit with adjuvant chemotherapy (ie, chemotherapy given after surgery) in resected stage IIA, IIB, and IIIA NSCLC, with a survival advantage of 5-10%. [104, 105] However, adjuvant chemotherapy in elderly patients with resected stage IIIA NSCLC is not associated with survival advantage. [106]

Two small, randomized trials have suggested that neoadjuvant chemotherapy (ie, chemotherapy given prior to surgery) prolongs survival in subjects with stage IIIA disease. Other similarly designed trials fail to confirm this.

Chemotherapy may be considered as part of multimodality therapy for locally advanced NSCLC and is used alone in the palliative treatment of stage IIIB NSCLC (owing to malignant pleural effusion) and stage IV NSCLC. [67] In advanced NSCLC, patients with good performance status (ie, 0-2 on the Zubrod or Eastern Cooperative Oncology Group [ECOG] scale) or greater than 70% on the Karnofsky scale; see the table below), and less than 10% body weight loss are good candidates for chemotherapy.

Non–small cell lung cancer. Performance status sca Non–small cell lung cancer. Performance status scales for patients with cancer.

Large meta-analyses from 16 randomized trials showed a significant survival advantage to patients getting chemotherapy as opposed to best supportive care. One-year survival in the chemotherapy arm was 29% as opposed to 20% in those receiving supportive care alone. This survival benefit was present irrespective of age or histology. There appears to be no detriment in quality of life in the patients treated with chemotherapy; hence, palliative chemotherapy should be offered to all patients who are willing and able to receive chemotherapy. [107, 108]

NSCLC is only moderately sensitive to chemotherapy, with single-agent response rates in the range of 15% or better. Newer agents (eg, gemcitabine, pemetrexed, docetaxel, vinorelbine) have shown promising single-agent activity, with response rates from 20-25%.

A study by Wanders et al found that patients with stage III NSCLC who are 75 years and older could have improved survival if they are provided treatment with curative intent (eg, radiotherapy only, sequential chemotherapy and radiation). [109] In an observational cohort study of patients aged 65 years or older, the benefit of adjuvant chemotherapy was similar to that seen with younger patients. However, a subset analysis of patients aged 80 years or older suggested that adjuvant chemotherapy might have more adverse effects in this population. [110]

Platinum-based regimens

Cisplatin has been the cornerstone of most combination regimens studied in advanced NSCLC. [111] A recent meta-analysis of 16 trials comparing platinum-based regimens to nonplatinum agents showed a statistically significant improved response rate as well as 1-year survival favoring cisplatin. A beneficial trend was noted with carboplatin-based combinations but this was not significant. Gastrointestinal toxicity was higher with cisplatin. [112]

American Society for Clinical Oncology (ASCO) guidelines recommend that first-line treatment for NSCLC should include a platinum combination. In younger patients, with a good performance status or in the adjuvant setting, cisplatin is preferred, but in older patients or those with significant comorbidities, carboplatin may be substituted. Some recent trials have studied nonplatinum combinations such as gemcitabine with a taxane, which have shown noninferiority, and may be an option for selected patients.

Several randomized controlled trials have failed to show a clear superiority of one platinum-containing combination over another. A landmark ECOG trial comparing cisplatin-gemcitabine, cisplatin-paclitaxel, cisplatin-docetaxel, and carboplatin-paclitaxel, suggested similar overall response rates (approximately 19%), and median survival (7.9 mo). One- and 2-year overall survival was also similar at 33% and 11%, respectively.

In October 2012, the US Food and Drug Administration (FDA) approved protein-bound paclitaxel (Abraxane) for locally advanced or metastatic NSCLC, as first-line treatment in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy. Approval was based on a single-phase, multicenter, randomized open-label study in which patients with advanced NSCLC received either weekly protein-bound paclitaxel plus carboplatin every 3 weeks or solvent-based paclitaxel plus carboplatin every 3 weeks. [113]

Patients who received the protein-bound paclitaxel demonstrated a statistically significantly higher overall response rate (ORR) compared with those in the solvent-based paclitaxel arm (33% vs 25%; P = .005). In patients with squamous histology, the ORR was also statistically superior in the protein-bound paclitaxel group (41% vs 24%; P < .001). There was no statistically significant difference in overall survival between the 2 study arms. [113]

The cisplatin-gemcitabine did appear to have an increased progression free survival, compared with the standard treatment arm of cisplatin-paclitaxel (4.2 mo vs 3.4 mo), with increased renal toxicity. This finding was confirmed by 2 Italian and Japanese studies, which showed similar efficacy of these combinations as measured by response rates or survival.

However, a meta-analysis comparing cisplatin-gemcitabine with other platinum-containing regimens suggested an improved median survival (9 vs 8.2 mo), and an absolute improvement in 1-year overall survival of 3.9% as compared with nongemcitabine combinations. This effect was not sustained when compared against other third-generation cisplatin combinations. [114]

A study by Quoix et al found that platinum-based doublet chemotherapy was associated with survival benefits among elderly patients with NSCLC compared with vinorelbine or gemcitabine monotherapy, despite increased toxic effects. [115] A separate study by Pallis et al found that chemotherapy treatment among older patients with NSCLC is feasible, with no significant differences in response compared with younger patients, although increased toxicity is noted. [116]

Histologic factors in chemotherapy responsiveness

For some time, NSCLC histology was thought to not impact chemotherapy responsiveness. A phase III trial comparing upfront cisplatin-pemetrexed with cisplatin-gemcitabine in stage III and IV NSCLC showed similar response rates (30.6% vs 28.2%), median survival (10.3 mo each), and 2-year overall survival (18.9% vs 14%). These were statistically similar.

However, in a preplanned subset analysis, median survival in patients with nonsquamous histology was significantly better with cisplatin-pemetrexed than with cisplatin-gemcitabine: 12.6 vs 10.9 mo for patients with adenocarcinoma and 10.4 vs 6.7 mo for those with large cell histology. In contrast, the patients with squamous cell histology did better with the cisplatin-gemcitabine combination: 10.8 vs 9.4 mo. Cisplatin-pemetrexed is now the preferred combination for adenocarcinoma. [117]

Genetic factors in resistance to platinum compounds

Although platinum-based chemotherapy is currently standard of care in NSCLC, data suggest that certain individual tumors may have inherent resistance to platinum compounds. Excision repair cross-complementation group 1 (ERCC1) is one such genetic abnormality, and high levels of ERCC1 messenger RNA in tumor tissue have been associated with resistance to platinum.

Holm et al found that, in patients receiving carboplatin and gemcitabine for inoperable NSCLC, the expression of ERCC1 had different effects on survival in men and women. In a retrospective study in 163 patients, men whose tumors were ERCC1 negative survived significantly longer than men with ERCC1 -positive tumors (median survival, 11.8 mo vs 7.9 mo). Conversely, ERCC1 status had no effect on survival in women. [118]

As with ERCC1, increased expression of ribonucleotide reductase subunit 1 (RRM1) has been associated with decreased response to gemcitabine and platinum.

In the future, therapy for NSCLC may need to be tailored on the basis of the genetic characteristics of individual tumors. Gene expression profiling has been studied for accurate classification of NSCLC histology as well as prognostication, but this remains experimental.

Second-line chemotherapy

Selected patients with good responses to first-line chemotherapy, good performance status, and a long disease-free period between initial chemotherapy and relapse may be candidates for second-line chemotherapy. Docetaxel and pemetrexed have been approved by the US Food and Drug Administration (FDA) in this clinical setting, but other drugs (eg, gemcitabine, vinorelbine), if not used in the first-line regimen, may result in similar palliation and clinical benefit.

In December 2014, the FDA approved ramucirumab (Cyramza) in combination with docetaxel for metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving ramucirumab.

Ramucirumab’s approval was based on improved overall survival (OS) in a multicenter, double-blind, placebo-controlled study (n = 1253) in patients with previously treated metastatic NSCLC. Patients were randomized to receive either ramucirumab (10 mg/kg q3wk) in combination with docetaxel (75 mg/m2 q3wk) on day 1 of a 21-day cycle (n=628) or matching placebo plus docetaxel (n=625). Results showed a statistically significant prolonged OS and PFS in patients treated with ramucirumab plus docetaxel. [119]

A phase III study published in 2009 compared immediate and delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced NSCLC and found a statistically significant improvement in progression-free survival when docetaxel was administered immediately after front-line gemcitabine plus carboplatin, without increasing toxicity or decreasing quality of life. The increase in overall survival was not statistically significant. [120]

Another phase III trial of pemetrexed versus docetaxel showed similar efficacy for both agents in recurrent NSCLC when administered as single-agent chemotherapy in second-line settings. Response rates (9.1% vs 8.8%) and overall survival (8.3 mo vs 7.9 mo) were similar. [121]

In a phase III study comparing docetaxel and docetaxel/aflibercept, the addition of ziv-aflibercept to standard docetaxel therapy did not improve overall survival in platinum-pretreated patients with advanced or metastatic nonsquamous NSCLC. [122]

Complications

Chemotherapy can give rise to various adverse effects, as follows:

  • Febrile neutropenia or bleeding from bone marrow suppression
  • Hyponatremia or hypomagnesemia from cisplatin nephrotoxicity
  • Renal failure or ototoxicity from cisplatin
  • Peripheral neuropathy from cisplatin, paclitaxel, and vinorelbine
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Combined Chemoradiation Therapy

The current standard of care in the management of good-risk (ie, Karnofsky performance score of 70-100, minimal weight loss) patients with locally advanced unresectable (stage IIIA) non–small cell lung cancer (NSCLC) is combined-modality therapy consisting of platinum-based chemotherapy in conjunction with radiation therapy. This combination results in statistically significant improvement in both disease-free and overall survival rates compared with either modality used alone. [123, 124]

Randomized studies show longer survival in patients with unresectable stage III disease when treated with concurrent (rather than sequential) platinum-based chemotherapy and radiation therapy. [125, 126] In a Radiation Therapy Oncology Group (RTOG) study that compared cisplatin/vinblastine either given concurrently with radiation therapy or followed by radiation therapy, the concurrent group showed better median survival as well as overall survival (17 vs 14.6 mo and 21% vs 12%, respectively). [127, 128, 129]

Chemotherapy regimens that have been studied in combination with radiation therapy include cisplatin/vinblastine and cisplatin/etoposide (5-y survival of 15%). [125] In elderly patients or those with comorbidities and contraindications to cisplatin, weekly carboplatin/paclitaxel may be used, based on a phase II study that showed a median survival of 16.7 months. [130, 131, 132]

Consolidation chemotherapy after chemoradiation had initially been shown to be beneficial in phase II studies, with docetaxel after chemoradiation with cisplatin/etoposide showing a median survival of 26 months and a 5-year survival of 29%. This regimen did not show improved survival in a phase III setting, and proved to be more toxic, hence, is no longer recommended outside a clinical trial setting. [133]

In a phase III study of 610 patients, treatment with a combination of cisplatin, etoposide, and radiation conferred significant overall survival. These researchers concluded that this regimen should be the standard among patients with stage III lung cancer. [134]

The high locoregional failure rate with chemoradiation alone has led to study of chemoradiation followed by surgical resection. [102, 104, 135] Uncontrolled phase II studies suggested possible survival benefit from this approach, but a phase III study showed only a nonsignificant trend toward better 5-year overall survival (27% vs 20%) despite an improvement in progression-free survival. The postoperative mortality rate was higher in those patients undergoing surgical resection.

A European Organization for Research and Treatment of Cancer (EORTC) study failed to show any benefit of resection over radiation therapy after neoadjuvant chemotherapy in patients with stage IIIA (N2) disease.

In a small study in patients who were node negative with T3 and T4 NSCLC, neoadjuvant chemoradiation followed by surgery led to better survival. [136]

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Molecular-Targeted Therapy

With the increased understanding of molecular abnormalities in lung cancer, research efforts have focused heavily on identifying molecular targets and using this knowledge to develop molecular-targeted therapies.

The possibility of finding a mutation that is susceptible to molecular-targeted therapy is driving more frequent mutation testing in NSCLC. However, the likelihood of a mutation depends on the histologic subtype of the cancer. Consequently, histologic testing should precede mutation testing. [87]

One such abnormality, which is common in NSCLC, is overexpression of the epidermal growth factor receptor (EGFR). Cancers overexpressing EGFR have been shown to have increased resistance to therapy, increased metastatic potential, and poorer prognoses.

Stimulation of the EGFR pathway leads to increased autophosphorylation of a tyrosine kinase pathway associated with EGFR. This leads to a series of intracellular events culminating in increased mitotic and growth potential, increased ability to metastasize, and increased angiogenesis (new blood vessel formation) in the cancer cells.

Rosell et al evaluated the feasibility of large-scale screening for EGFR mutations in patients with advanced NSCLC. EGFR mutations were found in 350 of 2105 patients (16.6%). Mutations were found more frequently in women (69.7%), patients who had never smoked (66.6%), and those with adenocarcinomas (80.9%). These researchers concluded that large-scale screening of patients with lung cancer for EGFR mutations is feasible and can have a role in decisions about treatment. [137]

The NCCN guidelines add that EGFR mutations are present in adenocarcinomas in approximately 10% of Western patients and up to 50% of Asian patients, and that the EGFR mutation frequency is higher in nonsmokers, women, and patients with non-mucinous cancers. In squamous cell carcinomas, however, the observed incidence of EGFR mutations is 2.7% and the true incidence can be confidently posited as less than 3.6%—too low to justify routine testing of all tumor specimens. [87]

Gefitinib

Gefitinib (Iressa) represents a class of EGFR tyrosine kinase inhibitors (TKIs) that act intracellularly to block activation of the EGFR pathway. [138, 139]

In July 2015, gefitinib returned to the United States market following restricted availability. It was approved by the FDA as first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. Approval as first-line treatment for metastatic NSCLC is based on data from the IFUM (IRESSA Follow-Up Measure) clinical trial, which showed an overall response rate (ORR) of about 50% with a median duration of response of 6 months. [140]

The IFUM results were supported by the most recent analysis of the IPASS (IRESSA Pan-ASia Study) study which assessed gefitinib vs. carboplatin/paclitaxel as a first-line treatment in these patients. The subset population consisted of 186 of 1217 patients (15%) determined to be EGFR positive by the same clinical trial assay as used in IFUM and had radiographic scans available for a retrospective assessment. IPASS showed an ORR of 67% with a median duration of response of 9.6 months in gefitinib-treated patients vs. 41% ORR with a median duration of response of 5.5 months for the carboplatin/paclitaxel group. Mean Progression Free Survival (PFS) was 10.8 months in the gefitinib group vs. 5.4 for the carboplatin/paclitaxel patients. [141]

Two large phase II trials led to the expedited original approval of gefitinib in the United States as a third-line therapy.

However, the Iressa Survival Evaluation in Lung Cancer (ISEL) trial, a large phase III randomized trial that compared gefitinib with placebo in patients who had progressed following first-line chemotherapy, found no significant improvement in median survival (5.6 vs 5.1 mo) overall and also in the adenocarcinoma subset (6.3 vs 5.4 mo). Planned subset analyses in patients who had never been smokers and those of Asian ethnicity showed significantly longer survival (8.9 vs 6.1 mo and 9.5 vs 5.5 mo) than with placebo. [139]

The INTEREST trial studied gefitinib versus docetaxel in the second-line setting and found no significant difference in survival (7.6 vs 8 mo). Based on these data, gefitinib was removed from the United States market for use in new patients and was only available by a restricted access program.

Mok et al conducted a large phase III study that compared gefitinib with carboplatin-paclitaxel in the first-line setting in Asian patients who had adenocarcinoma and had never smoked or were former light smokers (none in last 15 years). Patients receiving gefitinib had a higher response rate (43% vs 32%), with similar median survival (18.6 vs 17.3 mo). Of patients who were positive for the EGFR gene mutation, those in the gefitinib group had significantly longer progression-free survival than those in the carboplatin-paclitaxel group. Conversely, patients who were negative for the mutation had significantly longer progression-free survival with carboplatin-paclitaxel. [142]

In an early IPASS study, EGFR mutation was found to be the strongest predictor of progression-free survival and response to gefitinib. [143]

Erlotinib

A second EGFR TKI, erlotinib, improved survival rates compared with placebo in the second- and third-line setting. [144, 145] Erlotinib demonstrated improved response rates (8% vs < 1%), and overall survival (6.7 vs 4.6 mo). This led to the initial FDA approval of erlotinib in the second-line setting. As of late 2016, it is approved for NSCLC in patients whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test for first-line treatment, maintenance treatment, or as second or greater line treatment after progression following at least 1 prior chemotherapy regimen.

The 2015 NCCN guidelines recommend erlotinib (or afatinib) as first-line therapy in patients with documented EGFR mutations. [87] In an open-label, randomized, phase III trial of Chinese patients with adenocarcinoma of the lung with an EGFR mutation, progression-free survival was longer in patients treated with erlotinib than in those receiving standard chemotherapy with gemcitabine plus carboplatin (13.1 mo vs 4.6 mo). [146]

An open-label randomized phase III trial in European patients with NSCLC also found erlotinib to be superior to standard chemotherapy for first-line treatment of NSCLC with EGFR mutations. In this study, progression-free survival in patients with either of two specific types of EGFR mutations (exon 19 deletions or exon 21 [L858R] substitution mutations) was 9.7 months with erlotinib treatment, compared with 5.2 months for those who received standard therapy. [62]

Similar to the experience with gefitinib, no benefit was seen when erlotinib was combined with chemotherapy. Earlier studies also showed better response rates and survival with females, Asian persons, nonsmokers, particularly those with adenocarcinoma histology (especially bronchioalveolar cancer), as was seen with gefitinib.

In contrast, a study in 760 unselected patients with advanced NSCLC found that first-line treatment with erlotinib followed at disease progression by cisplatin-gemcitabine was significantly inferior in terms of overall survival compared with the standard sequence of chemotherapy with cisplatin-gemcitabine followed by erlotinib. [147]

A study by Herbst et al found no benefit when erlotinib was combined with bevacizumab compared with erlotinib alone in patients who experienced a failure of standard first-line chemotherapy. [148] A separate study by Hirsch et al compared the use of erlotinib alone or intercalated with chemotherapy among chemotherapy-naïve patients with advanced NSCLC who were positive for EGFR protein expression, had a high EGFR gene copy number, or both. The study results did not support combined chemotherapy and erlotinib in this setting; patients with tumors harboring EGFR mutations had better outcomes with erlotinib alone. [149]

Cetuximab

Cetuximab, a monoclonal antibody that binds the EGFR receptor, is also used in colorectal cancer and squamous cell cancer (SCC) of the head and neck. It was studied in the first-line setting, in combination with cisplatin-vinorelbine, compared with cisplatin-vinorelbine alone, in patients with NSCLC that expressed EGFR by immunohistochemistry. [150]

The chemotherapy was given in combination with cetuximab for up to 6 cycles, and in responding patients, the cetuximab was continued until progression. Patients receiving cetuximab had an increased response rate (36% vs 29%), and improved median survival (11.3 vs 10.1 mo). Whites appeared to benefit more than Asian persons, who seemed to do worse with this regimen.

A phase 3 study found that the addition of cetuximab to first-line chemotherapy in patients with advanced NSCLC provided a survival benefit in patients with high EGFR expression (immunohistochemistry score ≥ 200), increasing overall survival from a median of 9.6 to 12.0 months. No corresponding survival benefit was seen in those with low EGFR expression. [151]

Necitumumab

Necitumumab is another monoclonal antibody that binds to the human EFGR and blocks interaction between EGFR and its ligands. It was approved in November 2015 for first-line treatment of metastatic squamous NSCLC in combination with gemcitabine and cisplatin. Approval was based on the SQUIRE trial, conducted in 1093 patients, which showed a 1.6-month improvement in overall survival (OS) when necitumumab was added to a regimen of gemcitabine and cisplatin. The median OS was 11.5 months, compared with 9.9 months for gemcitabine and cisplatin alone. [152]

Vandetanib

A randomized, double-blind, phase III trial assessed the use of vandetanib, a once-daily oral inhibitor of vascular EGFR and EGFR signaling. [153] This second-line therapy did not meet the primary end point of statistically significant progression-free survival. However, the combination of vandetanib (100 mg/d) plus pemetrexed (500 mg/m2) was found to have a significantly higher objective response rate and a significant delay in time to worsening of symptoms compared with placebo. The combination also had an acceptable safety profile.

Bevacizumab

An ECOG study has shown that addition of the anti-angiogenesis agent bevacizumab (Avastin) to standard first-line carboplatin-paclitaxel resulted in significant prolongation of survival. Bevacizumab was continued in patients who appeared to respond to 4-6 cycles of chemotherapy. The median overall survival was improved (12.3-10.3 mo), as was the response rate (35% vs 15%) compared to chemotherapy alone.

Patients with squamous cell histology, brain metastases, clinically significant hemoptysis, and ECOG performance status of greater than 1 were excluded. Despite increased hemorrhagic complications and treatment-related deaths, bevacizumab has been approved for use in this setting in combination with chemotherapy. [154]

Bevacizumab has also been studied in combination with cisplatin-gemcitabine as first-line therapy for nonsquamous NSCLC, with improved response rates (20.1% vs 34.1%) and modest improvement in progression-free survival (6.7 vs 6.1 mo). Overall survival was not different. [155]

In a 2012 systematic review and meta-analysis of randomized phase II/III trials, adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced NSCLC significantly prolonged overall and progression-free survival. The effects of bevacizumab on overall survival were significantly greater in patients with adenocarcinoma versus other histologies. No unexpected toxicity was observed. [156]

Crizotinib

Crizotinib (Xalkori) was approved by the FDA in August 2011 for the treatment of locally advanced or metastatic NSCLC that is anaplastic lymphoma kinase (ALK) positive, as detected by the Vysis ALK Break Apart FISH Probe test (Abbott Molecular). Chromosomal rearrangement of ALK occurs in about 5% of NSCLC cases. Approval was based on 2 multicenter trials (n=255) in which median response duration ranged from 41.9-48.1 weeks. [157, 158]

In a study of patients with previously treated advanced NSCLC who had ALK gene rearrangement, treatment with crizotinib was superior to standard chemotherapy. [159, 160] Risk of progression was reduced by 50% with crizotinib. Study participants with locally advanced or metastatic ALK-positive lung cancer treated with one previous platinum-based regimen were randomized to oral crizotinib 250 mg twice daily or to chemotherapy with intravenous pemetrexed (500 mg/m²) or docetaxel (75 mg/m²) every 3 weeks. As part of a separate analysis, patients in the chemotherapy group with disease progression were allowed to cross over to crizotinib. [159, 160]

Median progression-free survival was longer with crizotinib treatment (7.7 mo) than with chemotherapy (3.0 mo). The hazard ratio for progression or death with crizotinib was 0.49 (95% confidence interval [CI], 0.37-0.64; P < 0.001), and the response rate was higher in the crizotinib group (65%) than in the chemotherapy group (20%) (P < 0.001). Overall survival was similar in the two groups. [159, 160]

In March 2016 the FDA expanded use of crizotinib to include patients with metastatic NSCLC whose tumors harbor a ROS-1 gene mutation. Study results showed crizotinib exhibited marked antitumor activity in this population with an objective response rate of 66% by an independent radiology review. There was 1 complete response and 32 partial responses. The median duration of response was 18.3 months. [161]

Brigatinib

Brigatinib (Alunbrig) was approved in April 2017 for ALK-positive metastatic NSCLC in patients who have progressed on or are intolerant to crizotinib. Approval was based on the noncomparative, open-label, multicenter ALTA clinical trial. After a median follow-up of 8 months, median duration of response was 13.8 months in patients randomized to receive brigatinib at oral doses of either 90 mg once daily (n = 112) or 180 mg once daily following a 7-day lead-in at 90 mg once daily (n = 110). [162]

Afatinib

Afatinib (Gilotrif) is a TKI that was approved by the FDA in July 2013 for first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by the diagnostic companion test therascreen EGFR RGQ PCR kit. [163, 164] Approval was based on data from the LUX-Lung 3 trial, in which progression-free survival in patients receiving afatinib was 11.1 months, compared with 6.9 months for those treated with pemetrexed/cisplatin. [163, 164]

Additionally, in patients with tumors expressing the two most common EGFR mutations (Del19 or L858R), progression-free survival was 13.6 months in those who received afatinib, versus 6.9 months for those in the chemotherapy arm. [163, 164]

In April 2016, the FDA approved afatinib for metastatic squamous NSCLC that has progressed after platinum-based chemotherapy. Approval was based on the LUX-Lung 8 clinical trial. Compared with erlotinib, afatinib obtained a significant delay in progression of lung cancer, reducing the risk of cancer progression by 18%. Also observed was a significant improvement in overall survival (p=0.0077), reducing the risk of death by 19%. A significantly improved disease control rate was also shown (51% vs 40%; P=0.002). [165]

The most common serious adverse events in patients receiving afatinib included diarrhea (6.6%), vomiting (4.8%), dyspnea, fatigue, and hypokalemia (1.7%). Fatal adverse events included pulmonary toxicity/interstitial lung disease (1.3%), sepsis (0.43%), and pneumonia (43%). [163, 164]

Ceritinib

Ceritinib, an ALK inhibitor, received accelerated approval from the FDA in 2014 for patients with ALK-positive metastatic NSCLC whose disease had progressed or who were intolerant to crizotinib based on a blinded independent review committee (BIRC)-assessed ORR of 44% among 163 patients in a single-arm trial. [166] A phase I study found that ceritinib at the dose of 400 mg daily provided a response rate of 58%, with a median progression-free survival of 7 months. Dose-limiting toxicity included diarrhea, vomiting, dehydration, elevated aminotransferase level, and hypophosphatemia. In this study, ceritinib was effective for both crizotinib-naive patients and those who had tumor progression with crizotinib. [167]

In May 2017, ceritinib was granted regular approved for patients with metastatic NSCLC whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. This approval also included use as first-line treatment. Approval was based on data from ASCEND-4, a randomized, multicenter, open-label, active-controlled trial conducted in patients with untreated ALK-positive NSCLC. All patients were required to have evidence of ALK-rearrangement identified by the VENTANA ALK (D5F3) test performed through central laboratory testing.

ASCEND-4 randomized 376 patients (1:1) to receive either ceritinib (n=189) 750 mg orally once daily until disease progression or platinum-pemetrexed doublet chemotherapy (n=187). Patients in the chemotherapy arm received pemetrexed (500 mg/m2) with either cisplatin (75 mg/m2) or carboplatin (AUC 5-6) on day 1 of every 21-day cycle for up to 4 cycles, followed by pemetrexed maintenance therapy. Results demonstrated improved PFS as assessed by BIRC, with a hazard ratio (HR) of 0.55 (p <0.0001). The estimated median PFS was 16.6 months in the ceritinib arm and 8.1 months in the chemotherapy arm. Confirmed ORR, was 73% and 27% in the ceritinib and chemotherapy arms, respectively. Estimated median response durations were 23.9 months and 11.1 months in the ceritinib and chemotherapy arms, respectively. Overall survival data are immature. [168]

Alectinib

The FDA granted accelerated approval of alectinib, a TKI that targets ALK and RET, in December, 2015. It is indicated for anaplastic lymphoma kinase (ALK)-positive, metastatic NSCLC in patients whose disease has progressed on crizotinib or who are intolerant to crizotinib.

Approval was based on two single-group studies in which alectinib was given to patients with metastatic ALK-positive NSCLC refractory to crizotinib. In the first study, 38% of 87 patients experienced a partial shrinkage of their NSCLC tumors, an effect that lasted for an average of 7.5 months. [169] In the second study, 44% of 138 patients experienced a partial shrinkage of their NSCLC tumors, lasting for an average of 11.2 months. [170]

The trials also examined the effect of alectinib on brain metastases, a common occurrence in this population. In both trials together, 61% of patients who had measurable brain metastases experienced a complete or partial reduction in their brain tumors, lasting an average of 9.1 months. [169, 170]

Third-generation agents

The biggest problem with agents directed against EGFR is that the tumor eventually develops resistance to the drugs. The EGFR T790M mutation is the most common mechanism of resistance to first-generation and second-generation EGFR TKIs. Several third-generation drugs have been developed to counteract this phenomenon, including rociletinib and osimertinib (now approved in the US). [171] Two unique characteristics of rociletinib are its ability to bind to T790M but not bind to wild-type EGFR, thus, causing milder adverse effects (eg, rash, diarrhea).in lung cancer

Osimertinib

Osimertinib is a kinase inhibitor of EGFR that binds irreversibly to certain mutant forms of EGFR (T790M, L858R, and exon 19 deletion). It was approved in the United States in November 2015 for metastatic  EGFR T790M mutation–positive NSCLC, as detected by an FDA-approved test, in patients who have progressed on or after EGFR TKI therapy. Approval was based on data from two AURA phase II studies (AURA extension and AURA2), which demonstrated efficacy in 411 patients whose disease had progressed on or after an EGFR TKI. In those trials, overall objective response rate (ORR) was 59% (95% CI: 54% to 64%). [172] A confirmatory phase III trial (AURA3) is ongoing.

Programmed cell death–1 inhibitors

Immune check point inhibitors such as programmed cell death (PD-1) inhibitors have gained increasing importance in cancer therapy. PD-1 is expressed on the surface of activated CD8+ T cells, and cancers that express PD-1 ligand (PDL-1) can inactivate these T cells and thus avoid attack by them. PD-1 inhibitors bind to PD-1, preventing the interaction with PD-1 ligand but not inactivating the T cell, so the T cells maintain their ability to target the cancer cells.

Nivolumab

Nivolumab (Opdivo) was approved for use in NSCLC in March 2015 for NSCLC with squamous pathology. Nivolumab is a monoclonal antibody inhibitor of PD-1. It is the first immunotherapy approved for NSCLC. Current NC CN guidelines recommend nivolumab as a treatment option in patients with squamous cell carcinoma that has progressed on first-line therapy. [87]  In October 2015, the FDA approved an expanded indication to include nonsquamous NSCLC.

FDA approval was supported by results from a clinical trial that was stopped early after showing a survival benefit, although the trial data have not yet been presented at a meeting or published. At the time, the company noted that that the trial (known as CheckMate 017) was conducted in 272 patients with advanced or metastatic squamous cell NSCLC and that it was open label. Patients were randomly assigned to treatment with either nivolumab 3 mg/kg IV every 2 weeks or docetaxel 75 mg/m² IV every 3 weeks. The FDA reported that the trial was designed to measure overall survival and found that patients who received nivolumab lived 3.2 months longer than those who received docetaxel. [173]

In an early phase I trial of nivolumab in a heavily pretreated group of patients, the response rate was 17%; at a dose of 3 mg/kg, the median overall survival was 14.9 months. Among those patients who responded, the responses were durable, with 24% alive at 24 months. The dose-limiting toxicity was pneumonitis, which resulted in three deaths. [96]

Pembrolizumab

In October 2015, a second PD-1 inhibitor, pembrolizumab (Keytruda), was approved for metastatic NSCLC. Approval of pembrolizumab was based in part on data from the KEYNOTE-001 trial, in which pembrolizumab produced an overall response rate of nearly 20% in 495 previously treated and treatment-naive patients with advanced or metastatic NSCLC. The overall response rate was much higher, at 45.2%, in a cohort of patients with NSCLC that showed high expression of PD-L1. The median duration of response exceeded 1 year (12.5 months) in all responders, regardless of the degree of PD-L1 expression. Median overall survival was 12.0 months (95% confidence interval [CI], 9.3–14.7 months) for all patients, 9.3 months (95% CI, 8.4–12.4 months) for previously treated patients, and 16.2 months (95% CI, 16.2 months–not reached) for previously untreated patients. [174]

In October 2016, pembrolizumab was approved for first-line treatment of patients with metastatic NSCLC whose tumors have high PD-L1 expression (Tumor Proportion Score [TPS] ≥50%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations. This expanded approval was based on results from the KEYNOTE-024 trial, which showed significantly longer PFS and OS and fewer adverse events with pembrolizumab than with platinum-based chemotherapy. Median progression-free survival was 10.3 months (95% CI, 6.7 to not reached) in the pembrolizumab group versus 6.0 months (95% CI, 4.2 to 6.2) in the chemotherapy group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.37 to 0.68; P<0.001). [175]

First-line combination treatment of pembrolizumab was approved in May 2017 for metastatic nonsquamous NSCLC. Approval was based on data from the KEYNOTE-021 trial (Cohort G1) in 123 previously untreated patients with metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations and irrespective of PD-L1 expression. In this trial, pembrolizumab plus pemetrexed and carboplatin demonstrated an ORR that was nearly double the ORR of pemetrexed/carboplatin (55% vs 29% respectively; all responses were partial responses). Among patients who received pembrolizumab plus pemetrexed/carboplatin, 93% had a duration of response of 6 months or more (range 1.4+ to 13.0+ months) compared to 81% who received pemetrexed/carboplatin alone (range 1.4+ to 15.2+ months). Progression free survival also improved (median 13.0 months [95% CI]) compared to 8.9 months (95% CI) with pemetrexed/carboplatin alone. [176]

In the KEYNOTE-010 trial, which compared pembrolizumab with docetaxel in 1034 patients with previously treated NSCLC who had PD-L1 expression on at least 1% of tumor cells, pembrolizumab resulted in longer overall survival and had a more favorable benefit-to-risk profile. In this randomized, open-label trial, median overall survival was 10.4 months with pembrolizumab 2 mg/kg, 12.7 months with pembrolizumab 10 mg/kg, and 8.5 months with docetaxel. [177]

Atezolizumab

In October 2016, atezolizumab (Tecentriq) was approved for patients with metastatic NSCLC who have disease progression during or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving atezolizumab. Atezolizumab is a monoclonal antibody to PD-L1. Approval was based on the phase III OAK and phase II POPLAR studies. In the OAK study, survival benefit of atezolizumab was compared with docetaxel chemotherapy, regardless of PD-L1 status. Patients receiving atezolizumab lived a median 4.2 months longer than those treated with docetaxel chemotherapy. [178, 179]

Figitumumab

In a phase II trial, Karp et al studied the effect of the anti–insulinlike growth factor 1 receptor antibody CP-751,871 (figitumumab) combined with paclitaxel and carboplatin in advanced treatment-naive NSCLC. Patients were randomized (2:1) to receive paclitaxel 200 mg/m2, carboplatin (area under the concentration-time curve [AUC] of 6), and CP-751,871 at a dose of 10 or 20 mg/kg (PCI[10] or PCI [20]); or paclitaxel and carboplatin alone (PC) every 3 weeks for up to 6 cycles. The PCI(20)/PC hazard ratio for progression-free survival was 0.8-0.56, indicating safety and efficacy in NSCLC. A randomized, open-label, phase III trial is currently under way. [180]

Combination targeted therapy

Dabrafenib with Trametinib

In June 2017, the FDA approved the combination of dabrafenib (a selective BRAF kinase inhibitor) and trametinib (an MEK1 inhibitor) for targeted treatment of metastatic NSCLC with BRAF V600E mutation. [181] Approval was based on a phase II open-label, nonrandomized study in patients who received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily in continuous 21-day cycles until disease progression.

Of the 93 patients in the study, 36 had received no prior systemic therapy for metastatic NSCLC, and 57 had demonstrated disease progression despite receiving at least one platinum-based chemotherapy regimen. In the previously treated group, the overall response rate (ORR) was 63% and the median duration of treatment response was 9.0 months. The overall disease control rate was 79% when patients who had stable disease for 12 weeks or more were included. [181]

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Stage-Based Management

Stage IA/IB (T1aN0M0 , T1bN0M0, T2aN0M0)

Surgery is the treatment of choice for stage I non–small cell lung cancer (NSCLC). A careful assessment of residual pulmonary reserve should be carried out as part of surgical planning. Although lobectomy is generally considered to be the optimal procedure, patients with limited pulmonary reserve may be considered for more limited intervention with either a segmental or a wedge resection. The risk of local recurrence is higher with limited resection, but no adverse effect on overall survival was reported in a randomized trial by the Lung Cancer Study Group.

Video-assisted thoracoscopic surgery (VATS) may be used for surgical resection. VATS offers apparently similar resection capability and decreased postoperative morbidity.

Patients with insufficient pulmonary reserve to undergo a resection may be treated with radiation therapy alone with curative intent. Retrospective data report a 5-year survival ranging from 10-25% with radiation therapy alone in this setting. Selected patients may be candidates for either stereotactic body radiotherapy or radiofrequency ablation for isolated lesions.

The role of postoperative radiation has been explored and a meta-analysis of 9 randomized trials revealed a reduction in overall survival with postoperative radiation therapy in stage I and II NSCLC. However, it remains to be seen whether the use of modern radiation techniques with better definition of target volume and cardiac sparing could alter these outcomes.

Adjuvant chemotherapy has been extensively explored in NSCLC. [182] A meta-analysis concluded that adjuvant cisplatin-based therapy improved survival in resected stage IB, II, and III NSCLC. The absolute benefit in survival at 5 years was 6.9%, but in subset analyses, the benefit in stage IB was not statistically significant. No impact of age, sex, histology, or type of surgery was noted. The CALGB 9633 study randomized resected stage IB patients to 4 cycles of carboplatin-paclitaxel versus observation.

This study initially showed improved overall survival at 4 years (71% vs 59%), but a longer term follow-up at 74 months showed no change in overall survival, except in patients with a tumor size greater than 4 cm. [183]

This contrasted with the results of a Canadian study that showed significantly improved 5-year survival for stage IB and II patients treated with adjuvant cisplatin-vinorelbine for 4 cycles. Patients with resected stage IB NSCLC should, therefore, be counseled about risks and benefits of adjuvant chemotherapy and may be offered either 4 cycles of platinum-based doublet chemotherapy, preferably cisplatin, or observation.

Stage IIA/IIB (T2bN0M0, T1aN1M0, T1bN1M0, T1bN1M0, T2aN1M0, T2bN1M0, T3N1M0)

Surgical resection is the treatment of choice for stage II NSCLC, except for those patients who are not surgical candidates because of comorbid conditions or poor pulmonary reserve.

Long-term survival of 10-25% has been reported in patients with radiation therapy alone delivered with curative intent. In such cases, however, the dose of radiation therapy should be approximately 60 Gy, with careful planning to define tumor volume and avoid critical structures. Frequently a cone-down boost is used to enhance local control.

Patient with resected stage II disease are candidates for platinum-based adjuvant chemotherapy (see below) and should be offered four cycles of platinum-based adjuvant chemotherapy.

Stage IIIA (T1aN2M0, T1bN2M0, T2aN2M0, T3N1M0, T3N2M0, T4N1M0)

The management of stage IIIA NSCLC is quite controversial. Surgical resection, chemotherapy, radiation therapy, or a combination of any of these modalities may be the optimal choice, depending on the clinical situation. Overall 5-year survival of stage IIIA (N2) ranges from 10-15%, as resectability rates are low and very few patients (5-10%) achieve long-term benefit with radiation therapy alone. Consequently, stage IIIA has been an area of active research.

Patients who have mediastinal node involvement (N2 or N3 stage) have poor results from surgery and hence should be considered for definitive chemoradiation therapy. Cisplatin-based combinations (eg, with etoposide) are preferred, with carboplatin an acceptable alternative in patients with contraindications to cisplatin. Radiation is usually given in daily fractions for a total of 60 Gy. A cone-down boost may be useful.

Hyperfractionation schedules appear to be better, but are not widely available. Further chemotherapy or surgery does not appear to provide significant survival benefit for in patients treated upfront with chemoradiation.

A large randomized trial conducted by the European Organisation for Research and Treatment of Cancer (EORTC) compared surgery versus radiation therapy following neoadjuvant chemotherapy and found no significant difference between the two approaches in stage IIIA N2 disease. Neoadjuvant chemotherapy followed by surgery may, however, be considered for younger patients with stage IIIA disease who have good performance status.

Patients with stage III (T3-4, N1) disease of the superior sulcus are usually treated with neoadjuvant chemotherapy followed by surgical resection Two-year survival in this group is 50-70%.

Patients with stage IIIA (T3, N1) disease who are candidates for surgical resection should be offered adjuvant chemotherapy after a definitive surgical resection, based on the results of the International Adjuvant Lung Trial (IALT) and meta-analysis of adjuvant chemotherapy trials showing a hazard ratio of 0.87 with adjuvant chemotherapy. These patients should also undergo a mediastinal node dissection. In patients with positive margins, radiation therapy may be considered concurrently with chemotherapy.

Several retrospective series have suggested that postoperative radiation therapy may improve local control in patients with involved mediastinal nodes. Prospective trials have yielded conflicting results with regard to reduction in local recurrence with postoperative radiation therapy. A meta-analysis of 9 randomized trials of postoperative radiation therapy did not find a survival benefit in the entire group or in the subgroup with N2 disease.

Two small reports have shown improvement in disease-free and overall survival rates with neoadjuvant cisplatin-based chemotherapy for stage IIIA NSCLC; this approach may be considered in patients with good performance status. This approach may also be employed for patients who have tumors that are too large for a radiation port, prior to definitive chemoradiation.

A phase III trial compared prophylactic cranial irradiation (PCI) versus observation in patients with stage III NSCLC. [184] The study determined that among patients with stage III disease who did not have progression of disease after treatment with surgery or radiation therapy, PCI decreased the rate of brain metastasis but did not improve overall survival or disease-free survival. No significant differences in global cognitive function or quality of life were noted after PCI; however, a significant decline in memory was noted at 1 year. [185]

Stage IIIB (T1aN3M0, T1bN3M0, T2aN3M0, T2bN3M0, T3N3M0, T4N2M0, T4N3M0)

Patients with satellite lesions (T4 N0-1) should undergo a surgical resection if possible, followed by adjuvant chemotherapy. All other patients with stage IIIB disease are usually not candidates for surgical resection and are best managed with chemotherapy, combined chemoradiation therapy, or radiation therapy alone, depending on extent of disease, sites of involvement, and performance status of the patient. Patients who have malignant pleural effusion are not candidates for radiation therapy and are managed as stage IV (see below).

In an open-label, phase III study in chemotherapy-naive patients with stage IIIB NSCLC (n=676), cetuximab combined with first-line taxane/carboplatin chemotherapy did not reach statistically significant improvement for progression-free survival or overall survival; however, significant improvement was shown in overall response rate. [186]

The NVALT3 study found that chemotherapy in patients aged 70 years or older treated with carboplatin/paclitaxel or carboplatin/gemcitabine did not have a decline in their quality of life. [187]

A meta-analysis of 10 randomized trials of combined chemoradiation therapy revealed a 10% reduction in risk of death with combined modality therapy compared with radiation alone. It appears that in appropriate candidates (with good performance status), chemotherapy given concurrently with radiation results in superior survival compared with chemotherapy followed by radiation therapy.

Patients with stage IIIB NSCLC and poor performance status are not good candidates for chemotherapy or a combined-modality approach. These patients may benefit from radiation therapy alone to palliate the symptoms of shortness of breath, cough, and hemoptysis. Patients with invasive airway obstruction may be candidates for palliative endobronchial curettage or stenting to relieve obstructive atelectasis and dyspnea.

Stage IV (Any T, any N, M1a; Any T, any N, M1b)

Patients with advanced NSCLC should be evaluated for the presence of distant metastases. Patients with solitary brain lesions may benefit from a surgical resection, or stereotactic radiosurgery, if their primary disease is well controlled. Isolated adrenal masses should be resected, since many adrenal masses are benign and even oligometastatic adrenal disease can occasionally be well controlled.

In a small study, patients with isolated adrenal metastasis from lung cancer treated with surgical resection compared with nonoperative management have a better 5-year survival (34% vs 0%). [188]

Isolated synchronous nodules (either in the same or the opposite lung) should be treated as two separate primaries. These patients may need PET scanning to identify occult metastases or serial scans prior to definitive surgical resection that may be counterproductive.

In first-line systemic therapy for stage IV disease, cisplatin-based regimens have provided clear evidence of improved median survival and reductions in risk of death. Patients with good performance status should be offered chemotherapy with a platinum-based combination. Older patients (>70 y) or those with contraindications may be treated with a carboplatin-based regimen, such as carboplatin-paclitaxel. Younger patients (< 70 y) with nonsquamous histology may be candidates for treatment with cisplatin-pemetrexed, which appears to be somewhat better than cisplatin-gemcitabine.

Patients with nonsquamous histology, absence of cranial metastases, and no hemoptysis may be candidates for treatment with bevacizumab, which has been studied in combination with carboplatin-paclitaxel and cisplatin-gemcitabine. Antiangiogenic therapy is very expensive and potentially toxic even in carefully selected patients; hence, a detailed discussion with patients about its modest benefits versus the risks and costs is important.

Two-drug combinations have been found to be superior to single-agent treatment. However, no therapeutic advantage is obtained with the use of three drugs.

No clear survival benefit is observed from maintenance non–cross-resistant chemotherapy, though this is being studied with agents such as pemetrexed. For example, a randomized, placebo-controlled, double-blind phase 3 study of maintenance therapy with pemetrexed in 663 patients with stage IIIB or IV disease who had not progressed on four cycles of platinum-based chemotherapy found that although pemetrexed therapy was associated with toxic effects, it significantly improved progression-free survival and overall survival compared with placebo. [189]

In other randomized, double-blind, placebo-controlled studies, quality of life during maintenance therapy with pemetrexed was similar to that seen with placebo, although a small increase in loss of appetite was observed. Pemetrexed maintenance therapy significantly delayed worsening of pain and hemoptysis and was associated with improvements in overall and progression-free survival, making it a treatment option for patients with advanced nonsquamous NSCLC who have not progressed after induction therapy with platinum-based regimens. [190, 191]

Small-molecule EGFR tyrosine kinase inhibitors such as gefitinib and erlotinib may benefit nonsmokers with adenocarcinomas, particularly bronchoalveolar carcinoma; women of Asian origin are particularly likely to benefit. In such patients, it may be helpful to evaluate for EGFR mutations and use these agents first line.

Similarly, patients with EGFR expression and absence of K -ras mutations may be considered for the addition of cetuximab to first-line chemotherapy. However, the combination of anti–vascular endothelial growth factor (VEGF) agents such as bevacizumab with anti-EGFR antibodies appears to detrimental in other settings, and its use in NSCLC should be avoided.

Patients with progressive disease and good performance status may be candidates for treatment with single cytotoxic drugs such as docetaxel, pemetrexed, or gemcitabine, if they were not exposed to these drugs in the first-line setting. Selected patients can also be treated with erlotinib, though this is typically used in the third-line setting.

Patients with ECOG/Zubrod performance scores greater than 2 should be considered for palliative care, focused on symptom control. These patients should be recommended for enrollment in hospice care programs.

American Society of Clinical Oncology (ASCO) guidelines on chemotherapy for stage IV disease includes the following recommendations [192] :

First-line therapy

  • Platinum-doublet therapy for patients with PS 0 to 1 (bevacizumab may be added to carboplatin plus paclitaxel if no contraindications)
  • Combination or single-agent chemotherapy or palliative care alone for patients with PS 2
  • Afatinib, erlotinib, or gefitinib for patients with sensitizing  EGFR mutations
  • Crizotinib for patients with  ALK or  ROS1 gene rearrangement
  • Other recommended first-line regimens or platinum plus etoposide for patients with large-cell neuroendocrine carcinoma

Maintenance therapy 

  • Pemetrexed continuation for patients with stable disease or response to first-line pemetrexed-containing regimens
  • Alternative chemotherapy
  • A chemotherapy break

Second-line therapy 

  • Docetaxel, erlotinib, gefitinib, or pemetrexed for patients with nonsquamous cell carcinoma
  • Docetaxel, erlotinib, or gefitinib for patients with squamous cell carcinoma
  • Chemotherapy or ceritinib for those with  ALK rearrangement who experience progression after crizotinib

Third-line therapy

  • Treatment with erlotinib for patients who have not received erlotinib or gefitinib.

Patients with large-cell neuroendocrine carcinoma should receive platinum plus etoposide or the same treatment as other patients with nonsquamous carcinoma.

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Physical Activity

A patient's activity level, as measured by a performance status scale (eg, Zubrod, Karnofsky) is an important prognostic factor. Patients should be encouraged to remain active during and after treatment for lung cancer. A declining activity level usually signifies progressive or recurrent disease but also may be due to adverse effects of treatment.

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Prevention of NSCLC

Smoking cessation

Cigarette smoking is the most common etiologic factor for lung cancer; thus, the primary way to decrease the prevalence of lung cancer is to decrease the prevalence of smoking. Some measures for doing so include the following:

  • Public education about the hazards of smoking
  • More stringent legislation for tobacco control, including the increase of tax levies
  • Banning of tobacco smoking in public areas - Exposure to second-hand smoke and other respiratory toxins in the workplace has decreased as a result of federal legislation
  • Offering comprehensive strategies for smoking cessation to smokers, which include behavioral counseling, pharmaceutical aids such as varenicline, bupropion, and nicotine replacement therapy (eg, gum, transdermal patches)

Combining nicotine replacement, bupropion, and social or behavioral support can increase the quit rate to 35%. [193]

Although the relative risk of cancer does not decline to baseline levels for as long as 10 years after cessation, linked conditions (eg, chronic bronchitis, chronic obstructive pulmonary disease) show more rapid improvement or stabilization. [194]

Other measures

Workers exposed to asbestos or radioactive materials should always wear required safety equipment.

Some studies have shown a reduction in lung cancer incidence with daily use of aspirin. This reflects similar studies showing as association between use of nonsteroidal anti-inflammatory drugs (NSAIDs) and a reduced incidence of colorectal cancer and adenoma. [195]

Screening

Prevention is the more effective modality for decreasing the prevalence of NSCLC. However, several organizations recommend screening with low-dose computed tomography in patients at high risk for lung cancer. See the Screening subsection in Workup.

 

 

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Consultations

The management of lung cancer is best achieved with a multidisciplinary approach; therefore, after diagnosis, consultations should be sought from the following specialists:

  • Thoracic surgeon
  • Radiation oncologist
  • Medical oncologist
  • Pulmonologist
  • Social worker

To address complications caused by spread of the disease, consultation with one or more of the following services may be needed:

  • Otolaryngology
  • General surgery
  • Orthopedic surgery
  • Vascular surgery
  • Neurosurgery
  • Neurology
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Long-Term Monitoring

Recommendations from the National Comprehensive Cancer Network (NCCN) regarding cancer surveillance in survivors of non–small cell lung cancer (NSCLC) include the following [87] :

  • History and physical examination (H&P) and chest computed tomography (CT) scan with or without contrast every 6-12 months for 2 years, then an H&P and noncontrast chest CT scan annually
  • Assessment of smoking status at each visit, with counseling and referral for smoking cessation as needed

Other NCCN recommendations for long-term monitoring include the following [87] :

  • Annual influenza vaccination; pneumococcal vaccination with revaccination as appropriate; herpes zoster vaccination
  • Counseling regarding health promotion and wellness (eg, regular physical activity, healthy diet)
  • Routine health monitoring
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