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Non-Small Cell Lung Cancer Treatment (Professional) (cont.)

Stage IV NSCLC Treatment

Forty percent of patients with newly diagnosed non-small cell lung cancer (NSCLC) have stage IV disease. Treatment goals are to prolong survival and control disease-related symptoms. Treatment options include cytotoxic chemotherapy and targeted agents. Factors influencing treatment selection include comorbidity, performance status (PS), histology, and molecular genetic features of the cancer. Radiation therapy and surgery are generally used in selective cases for symptom palliation.

Standard Treatment Options for Stage IV NSCLC

Standard treatment options for stage IV NSCLC include the following:

  1. Cytotoxic combination chemotherapy (first line) with platinum (cisplatin or carboplatin) and paclitaxel, gemcitabine, docetaxel, vinorelbine, irinotecan, and pemetrexed.
    1. Factors influencing treatment.
      • Histology.
      • Age versus comorbidity.
      • PS.
  2. Combination chemotherapy with bevacizumab or cetuximab.
  3. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (first line) (for patients with EGFR mutations).
  4. EML4-ALK inhibitors in patients with EML-ALK translocations.
  5. Maintenance therapy following first-line chemotherapy (for patients with stable or responding disease following four cycles of non–pemetrexed-platinum combination chemotherapy).
  6. Endobronchial laser therapy and/or brachytherapy (for obstructing lesions).[1]
  7. External-beam radiation therapy (EBRT) (primarily for palliation of local symptomatic tumor growth).[2,3,4]

Randomized controlled trials of patients with stage IV disease and good PS have shown that cisplatin-based chemotherapy improves survival and palliates disease-related symptoms.[5][Level of evidence: 1iiA] Patients with nonsquamous cell histology, good PS, no history of hemoptysis or other bleeding, or recent history of cardiovascular events may benefit from the addition of bevacizumab to paclitaxel and carboplatin. Patients with tumors harboring mutations in EGFR, particularly those from East Asia, never smokers, and those with adenocarcinoma may benefit from EGFR tyrosine kinase inhibitors as an alternative to first- or second-line chemotherapy. Second-line chemotherapy with docetaxel, pemetrexed, or erlotinib also improves survival in patients with good PS.[5][Level of evidence: 1iiA] The role of chemotherapy in patients with poor PS was less certain.

Cytotoxic combination chemotherapy (first line)

The type and number of chemotherapy drugs to be used for the treatment of patients with advanced NSCLC has been extensively evaluated in randomized controlled trials and meta-analyses.

Several randomized trials have evaluated various drugs combined with either cisplatin or carboplatinum in previously untreated patients with advanced NSCLC. Based on meta-analyses of the trials, the following conclusions can be drawn:

  • Certain three-drug combinations that add so-called targeted agents may result in superior survival.
  • EGFR inhibitors may benefit selected patients with EGFR mutations.
  • Maintenance chemotherapy following four cycles of platinum combination chemotherapy may improve progression-free survival (PFS).
  • Platinum combinations with vinorelbine, paclitaxel, docetaxel, gemcitabine, irinotecan, and pemetrexed yield similar improvements in survival. Types and frequencies of toxic effects differ, and these may determine the preferred regimen for an individual patient. Patients with adenocarcinoma may benefit from pemetrexed.
  • Cisplatin and carboplatinum yield similar improvements in outcome with different toxic effects. Some, but not all, trials and meta-analyses of trials suggest that outcomes with cisplatin may be superior, although with a higher risk of certain toxicities such as nausea and vomiting.
  • Nonplatinum combinations offer no advantage to platinum-based chemotherapy, and some studies demonstrate inferiority.
  • Three-drug combinations of the commonly used chemotherapy drugs do not result in superior survival and are more toxic than two-drug combinations.

Evidence (combination chemotherapy):

  1. The Cochrane Collaboration group reviewed data from all randomized controlled trials published between January 1980 and June 2006, comparing a doublet regimen with a single-agent regimen or comparing a triplet regimen with a doublet regimen in patients with advanced NSCLC.[6] Sixty-five trials (13,601 patients) were identified.
    1. In the trials comparing a doublet regimen with a single-agent regimen, a significant increase was observed in tumor response (odds ratio [OR], 0.42; 95% confidence interval [CI], 0.37– 0.47; P < .001) and 1-year survival (OR, 0.80; 95% CI, 0.70–0.91; P < .001) in favor of the doublet regimen. The absolute benefit in 1-year survival was 5%, which corresponds to an increase in 1-year survival from 30% with a single-agent regimen to 35% with a doublet regimen. The rates of grades 3 and 4 toxic effects caused by doublet regimens were statistically increased compared with rates following single-agent therapy, with ORs ranging from 1.2 to 6.2. There was no increase in infection rates in doublet regimens.
    2. There was no increase in 1-year survival (OR, 1.01; 95% CI, 0.85–1.21; P = .88) for triplet regimens versus doublet regimens. The median survival ratio was 1.00 (95% CI, 0.94–1.06; P = .97).
  2. Several meta-analyses have evaluated whether cisplatin or carboplatin regimens are superior with variable results.[7,8,9] One meta-analysis reported individual patient data for 2,968 patients entered in nine randomized trials.[7]
    1. The objective response rate was higher for patients treated with cisplatin than for patients treated with carboplatin (30% vs. 24%, respectively; OR, 1.37; 95% CI, 1.16–1.61; P < .001).
    2. Carboplatin treatment was associated with a non–statistically significant increase in the hazard of mortality relative to treatment with cisplatin (hazard ratio [HR], 1.07; 95% CI, 0.99–1.15; P = .100).
    3. In patients with nonsquamous tumors and those treated with third-generation chemotherapy, carboplatin-based chemotherapy was associated with a statistically significant increase in mortality (HR, 1.12; 95% CI, 1.01–1.23 and HR, 1.11; 95% CI, 1.01–1.21, respectively).
    4. Treatment-related toxic effects were also assessed in the meta-analysis. More thrombocytopenia was seen with carboplatin than with cisplatin (12% vs. 6%; OR, 2.27; 95% CI, 1.71–3.01; P < .001), while cisplatin caused more nausea and vomiting (8% vs. 18%; OR, 0.42; 95% CI, 0.33–0.53; P < .001) and renal toxic effects (0.5% vs. 1.5%; OR, 0.37; 95% CI, 0.15–0.88; P = .018).
    5. The authors concluded that treatment with cisplatin was not associated with a substantial increase in the overall risk of severe toxic effects. This comprehensive individual-patient meta-analysis is consistent with the conclusions of other meta-analyses, which were based on essentially the same clinical trials but which used only published data.
  3. Three literature-based meta-analyses have trials comparing platinum with nonplatinum combinations.[10,11,12]
    1. The first meta-analysis identified 37 assessable trials that included 7,633 patients.[10]
      • A 62% increase in the OR for response was attributable to platinum-based therapy (OR, 1.62; 95% CI, 1.46–1.8; P < .001). The 1-year survival rate was increased by 5% with platinum-based regimens (34% vs. 29%; OR, 1.21; 95% CI, 1.09–1.35; P = .003).
      • No statistically significant increase in 1-year survival was found when platinum therapies were compared with third-generation-based combination regimens (OR, 1.11; 95% CI, 0.96–1.28; P = .17).
      • The toxic effects of platinum-based regimens was significantly higher for hematologic toxic effects, nephrotoxic effects, and nausea and vomiting but not for neurologic toxic effects, febrile neutropenia rate, or toxic death rate. These results are consistent with the second literature-based meta-analysis.
    2. The second meta-analysis identified 17 trials that included 4,920 patients.[11]
      • The use of platinum-based doublet regimens was associated with a slightly higher survival at 1 year (relative risk [RR], 1.08; 95% CI, 1.01%–1.16%; P = .03) and a better partial response (RR, 1.11; 95% CI, 1.02–1.21; P = .02), with a higher risk of anemia, nausea, and neurologic toxic effects.
      • In subanalyses, cisplatin-based doublet regimens improved survival at 1 year (RR, 1.16%; 95% CI, 1.06–1.27; P = .001), complete response (RR, 2.29; 95% CI, 1.08–4.88; P = .03), and partial response (RR, 1.19; 95% CI, 1.07–1.32; P = .002), with an increased risk of anemia, neutropenia, neurologic toxic effects, and nausea.
      • Conversely, carboplatin-based doublet regimens did not increase survival at 1 year (RR, 0.95; 95% CI, 0.85–1.07; P = .43).
    3. The third meta-analysis of phase III trials randomizing platinum-based versus nonplatinum combinations as first-line chemotherapy identified 14 trials.[12] Experimental arms were gemcitabine and vinorelbine (n = 4), gemcitabine and taxane (n = 7), gemcitabine and epirubicin (n = 1), paclitaxel and vinorelbine (n = 1), and gemcitabine and ifosfamide (n = 1). This meta-analysis was limited to the set of 11 phase III studies that used a platinum-based doublet (2,298 and 2,304 patients in platinum-based and nonplatinum arms, respectively).
      • Patients treated with a platinum-based regimen benefited from a statistically significant reduction in the risk of death at 1 year (OR, 0.88; 95% CI, 0.78–0.99; P = .044) and a lower risk of being refractory to chemotherapy (OR, 0.87; CI, 0.73–0.99; P = .049).
      • Forty-four (1.9%) and 29 (1.3%) toxic-related deaths were reported for platinum-based and nonplatinum regimens, respectively (OR, 1.53; CI, 0.96–2.49; P = 0.08). An increased risk of grade 3-4 gastrointestinal and hematologic toxic effects for patients treated with platinum-based chemotherapy was statistically demonstrated. There was no statistically significant increase in risk of febrile neutropenia (OR, 1.23; CI, 0.94–1.60; P = .063).

Among the active combinations, definitive recommendations regarding drug dose and schedule cannot be made, with the exception of pemetrexed for patients with adenocarcinoma.

Evidence (drug and dose schedule):

  1. There has been one meta-analysis of seven trials that included 2,867 patients to assess the benefit of docetaxel versus vinorelbine.[13] Docetaxel was administered with a platinum agent in three trials, with gemcitabine in two trials, or as monotherapy in two trials. Vinca alkaloid (vinorelbine in six trials and vindesine in one trial) was administered with cisplatin in six trials or alone in one trial.
    • The pooled estimate for overall survival (OS) showed an 11% improvement in favor of docetaxel (HR, 0.89; 95% CI, 0.82–0.96; P = .004). Sensitivity analyses that considered only vinorelbine as a comparator or only the doublet regimens showed similar improvements.
    • Grade 3 to 4 neutropenia and grade 3 to 4 serious adverse events were less frequent with docetaxel-based regimens versus vinca alkaloid-based regimens (OR, 0.59; 95% CI, 0.38–0.89; P = .013 and OR, 0.68; 95% CI, 0.55–0.84; P < .001, respectively).
  2. There have been two randomized trials comparing weekly versus every 3 weeks' dosing of paclitaxel and carboplatin, which reported no significant difference in efficacy and better tolerability for weekly administration.[14,15] Although meta-analyses of randomized controlled trials suggest that cisplatin combinations may be superior to carboplatin or nonplatinum combinations, the clinical relevance of the differences in efficacy must be balanced against the anticipated tolerability, logistics of administration, and familiarity of the medical staff for treatment decisions for individual patients.
  3. A large, noninferiority, phase III randomized study compared the OS in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and a PS of 0 to 1.[16] Patients received cisplatin 75 mg/m2 on day 1 and gemcitabine 1,250 mg/m2 on days 1 and 8 (n = 863) or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day 1 (n = 862) every 3 weeks for up to six cycles.
    • OS for cisplatin and pemetrexed was noninferior to cisplatin and gemcitabine (median survival, 10.3 mo vs. 10.3 mo, respectively; HR, 0.94; 95% CI, 0.84%–1.05%).
    • OS was statistically superior for cisplatin and pemetrexed versus cisplatin and gemcitabine in patients with adenocarcinoma (n = 847; 12.6 mo vs. 10.9 mo, respectively) and large cell carcinoma histology (n = 153; 10.4 mo vs. 6.7 mo, respectively).
    • In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin and gemcitabine versus cisplatin and pemetrexed (n = 473; 10.8 mo vs. 9.4 mo, respectively). For cisplatin and pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P = .001); febrile neutropenia (P = .002); and alopecia (P < .001) were significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common.
    • This study suggests that cisplatin and pemetrexed are another alternative doublet for first-line chemotherapy for advanced NSCLC and also suggests that there may be differences in outcome depending on histology.

Factors influencing treatment


Patients with adenocarcinoma may benefit from pemetrexed,[16] EGFR inhibitors, and bevacizumab.

Age versus comorbidity

Evidence supports that elderly patients with good PS and limited comorbidity may benefit from combination chemotherapy. Age alone should not dictate treatment-related decisions in patients with advanced NSCLC. Elderly patients with a good PS enjoy longer survival and a better quality of life when treated with chemotherapy compared with supportive care alone. Caution should be exercised when extrapolating data for elderly patients (aged 70–79 years) to patients aged 80 years or older because only a very small number of patients aged 80 years or older have been enrolled on clinical trials, and the benefit in this group is uncertain.[17,18]

Evidence (age vs. comorbidity):

  1. Platinum-containing combination chemotherapy regimens provide clinical benefit when compared with supportive care or single-agent therapy; however, such treatment may be contraindicated in some older patients because of the age-related reduction in the functional reserve of many organs and/or comorbid conditions. Approximately two-thirds of patients with NSCLC are aged 65 years or older and approximately 40% are aged 70 years or older.[19] Surveillance, Epidemiology, and End Results (SEER) data suggest that the percentage of patients aged older than 70 years is closer to 50%.
  2. A review of the SEER Medicare data from 1994 to 1999 found a much lower rate of chemotherapy use than expected for the overall population.[20] It also suggested that elderly patients may have more comorbidities or a higher rate of functional compromise that would make study participation difficult, if not contraindicated, and lack of clinical trial data may influence decisions to treat individual patients with standard chemotherapy.
  3. Single-agent chemotherapy and combination chemotherapy clearly benefit at least some elderly patients. In the Elderly Lung Cancer Vinorelbine Italian Study, 154 patients who were older than 70 years were randomly assigned to vinorelbine or supportive care.[21]
    • Patients who were treated with vinorelbine had a 1-year survival rate of 32%, compared with 14% for those who were treated with supportive care alone. Quality-of-life parameters were also significantly improved in the chemotherapy arm, and toxic effects were acceptable.
  4. A more recent trial from Japan compared single-agent docetaxel with vinorelbine in 180 elderly patients with good PS.[22]
    • Response rates and PFS were significantly better with docetaxel (22% vs. 10%; 5.4 mo vs. 3.1 mo, respectively), whereas median and 1-year survival rates did not reach statistical significance (14.3 mo vs. 9.9 mo; 59% vs. 37%, respectively).
  5. Retrospective data analyzing and comparing younger (age <70 years) patients with older (age =70 years) patients who participated in large, randomized trials of doublet combinations have also shown that elderly patients may derive the same survival benefit, although with a higher risk of toxic effects in the bone marrow.[17,18,23,24,25,26]

Performance status (PS)

PS is among the most important prognostic factors for survival of patients with NSCLC.[27] The benefit of therapy for this group of patients has been evaluated through retrospective analyses as well as through prospective clinical trials.

The results support further evaluation of chemotherapeutic approaches for both metastatic and locally advanced NSCLC; however, the efficacy of current platinum-based chemotherapy combinations is such that no specific regimen can be regarded as standard therapy. Outside of a clinical trial setting, chemotherapy should be given only to patients with good PS and evaluable tumor lesions, who desire such treatment after being fully informed of its anticipated risks and limited benefits.

Evidence (performance status):

  1. The Cancer and Leukemia Group B trial (CLB-9730), which compared carboplatin and paclitaxel with single-agent paclitaxel, enrolled 99 patients with a PS of 2 (18% of the study's population).[25]
    • When compared with patients with a PS of 0 to 1, who had a median survival of 8.8 months and a 1-year survival of 38%, the corresponding figures for patients with a performance status of 2 were 3.0 months and 14%, respectively; this demonstrates the poor prognosis conferred by a lower PS. These differences were statistically significant.
    • When patients with a PS of 2 were analyzed by treatment arm, those who received combination chemotherapy had a significantly higher response rate (24% vs. 10%), longer median survival (4.7 mo vs. 2.4 mo), and superior 1-year survival (18% vs. 10%), compared with those who were treated with single-agent paclitaxel.[25]
  2. A subset analysis of 68 patients with a PS of 2 from a trial that randomly assigned more than 1,200 patients to four platinum-based regimens has been published.
    • Despite a high incidence of adverse events, including five deaths, the final analysis showed that the overall toxic effects experienced by patients with a PS of 2 was not significantly different from that experienced by patients with a PS of 0 to 1.
    • An efficacy analysis demonstrated an overall response rate of 14%, median survival time of 4.1 months, and a 1-year survival rate of 19%; all were substantially inferior to the patients with PS of 0 to 1.
  3. A phase II randomized trial (E-1599) of attenuated dosages of cisplatin plus gemcitabine and carboplatin plus paclitaxel included 102 patients with a PS of 2.[28]
    • Response rates were 25% and 16%, median survival times were 6.8 months and 6.1 months, and 1-year survival rates were 25% and 19%, respectively. None of these differences was statistically significant, but the survival figures were longer than expected on the basis of historical controls.
  4. Results from two trials suggest that patients with a PS of 2 may experience symptom improvement.[29,30]

Combination chemotherapy with bevacizumab or cetuximab

Evidence (combination chemotherapy with bevacizumab or cetuximab):

  1. Two randomized trials have evaluated the addition of bevacizumab, an antibody targeting vascular endothelial growth factor, to standard first-line combination chemotherapy.
    1. In a randomized study of 878 patients with recurrent or advanced stage IIIB or stage IV NSCLC, 444 patients received paclitaxel and carboplatin alone, and 434 patients received paclitaxel and carboplatin plus bevacizumab.[31] Chemotherapy was administered every 3 weeks for six cycles, and bevacizumab was administered every 3 weeks until disease progression was evident or toxic effects were intolerable. Patients with squamous cell tumors, brain metastases, clinically significant hemoptysis, or inadequate organ function or PS (ECOG PS >1) were excluded.
      • The median survival was 12.3 months in the group assigned to chemotherapy plus bevacizumab, as compared with 10.3 months in the chemotherapy-alone group (HR for death, 0.79; P = .003).
      • The median PFS in the two groups was 6.2 months and 4.5 months, respectively (HR for disease progression, 0.66; P < .001), with corresponding response rates of 35% and 15%, respectively (P < .001).
      • Rates of clinically significant bleeding were 4.4% and 0.7%, respectively (P < .001). There were 15 treatment-related deaths in the chemotherapy-plus-bevacizumab group, including five from pulmonary hemorrhage.
      • For this subgroup of patients with NSCLC, the addition of bevacizumab to paclitaxel and carboplatin may provide survival benefit.[31][Level of evidence: 1iiA]
    2. Another randomized phase III trial investigated the efficacy and safety of cisplatin/gemcitabine plus bevacizumab.[32] Patients were randomly assigned to receive cisplatin (80 mg/m2) and gemcitabine (1,250 mg/m2) for up to six cycles, plus low-dose bevacizumab (7.5 mg/kg), high-dose bevacizumab (15 mg/kg), or placebo every 3 weeks until disease progression. The primary endpoint was amended from OS to PFS during the course of the study. A total of 1,043 patients were accrued (placebo group, n = 347; low-dose group, n = 345; high-dose group, n = 351).
      • PFS was significantly prolonged; the HRs for PFS were 0.75 (median PFS, 6.7 mo vs. 6.1 mo for placebo group; P = .03) in the low-dose group and 0.82 (median PFS, 6.5 mo vs. 6.1 mo for placebo group; P = .03) in the high-dose group compared with the placebo group.[32][Level of evidence: 1iiB]
      • Objective response rates were also improved with the addition of bevacizumab, and they were 20.1%, 34.1%, and 30.4% for placebo, low-dose bevacizumab, and high-dose bevacizumab plus cisplatin/gemcitabine, respectively.
      • Incidence of grade 3 or greater adverse events was similar across arms.
      • Grade 3 or greater pulmonary hemorrhage rates were 1.5% or less for all arms, despite 9% of patients receiving therapeutic anticoagulation.
      • These results support the addition of bevacizumab to platinum-containing chemotherapy, but the results are far less impressive than when the carboplatin-paclitaxel combination was used.
      • Furthermore, no significant difference in survival was shown in this study, as reported in abstract form.
      • Altogether, these findings may suggest that the backbone of chemotherapy may be important when bevacizumab is added.
  2. Two trials have evaluated the addition of cetuximab to first-line combination chemotherapy.[33,34]
    1. In the first trial, 676 chemotherapy-na´ve patients with stage IIIB (pleural effusion) or stage IV NSCLC, without restrictions by histology or EGFR expression, received cetuximab with taxane (paclitaxel or docetaxel with carboplatin) or combination chemotherapy.[33]
      • The addition of cetuximab did not result in a statistically significant improvement in PFS, the primary study endpoint, or OS.
      • Median PFS was 4.40 months with cetuximab/chemotherapy versus 4.24 months with taxane/carboplatin (HR, 0.902; 95% CI, 0.761–1.069; P = .236).
      • Median OS was 9.69 months with cetuximab/chemotherapy versus 8.38 months with chemotherapy (HR, 0.890; 95% CI, 0.754–1.051; P = .169).
      • No significant associations were found between EGFR expression, EGFR mutation, EGFR copy number, or KRAS mutations and PFS, OS, and response in the treatment-specific analyses.[35]
    2. The second trial was composed of 1,125 chemotherapy-na´ve patients with advanced EGFR-expressing stage IIIB or stage IV NSCLC treated with cisplatin/vinorelbine chemotherapy plus cetuximab or chemotherapy alone.[34]
      • The primary study endpoint, OS, was longer for patients treated with cetuximab and chemotherapy (median 11.3 months vs. 10.1 months; HR for death, 0.871; 95% CI, 0.762–0.996; P = .044).
      • A survival benefit was seen in all histological subgroups; however, survival benefit was not seen in non-white or Asian patients. Only the interaction between the treatment and the ethnic origin was significant (P = .011).
      • The main cetuximab-related adverse event was acne-like rash (10%, grade 3).
    3. It is not clear whether the differences in outcome in these two studies are the result of differences in the study populations, tumor characterization for EGFR expression, or chemotherapy regimens.

EGFR tyrosine kinase inhibitors (first line)

Selective patients may benefit from single-agent EGFR tyrosine kinase inhibitors. Randomized controlled trials of patients with chemotherapy-na´ve NSCLC and EGFR mutations have shown that EGFR inhibitors improved PFS but not OS and have favorable toxicity profiles compared with combination chemotherapy.

Evidence (EGFR tyrosine kinase inhibitors):

  1. A phase III, multicenter, randomized trial compared gefitinib with carboplatin plus paclitaxel as first-line treatment in clinically selected patients in East Asia who had advanced adenocarcinoma of the lung and had never smoked or were former light smokers.[36]
    1. The study met its primary objective of demonstrating the superiority of gefitinib as compared with the carboplatin-paclitaxel combination for PFS (HR for progression or death, 0.74; 95% CI, 0.65–0.85; P < .001).
    2. The median PFS was 5.7 months in the gefitinib group and 5.8 months in the carboplatin-paclitaxel group.[36][Level of evidence: 1iDiii]
    3. Following the time that chemotherapy was discontinued and while gefitinib was continued, the PFS curves clearly separated and favored gefitinib.
      • The 12-month PFS rates were 24.9% with the gefitinib group and 6.7% with the carboplatin-paclitaxel group.
    4. More than 90% of the patients in the trial with mutations had either del19 or exon 21 L858R mutations, which have been shown to be sensitive to EGFR inhibitors. In the subgroup of patients with a mutation, PFS was significantly longer among those who received gefitinib (HR, 0.48; 95% CI, 0.36–0.64; P < .001), whereas, in the subgroup of patients who were negative for a mutation, PFS was significantly longer in those who received the carboplatin-paclitaxel combination (HR with gefitinib, 2.85; 95% CI, 2.05–3.98; P < .001). There was a significant interaction between treatment and EGFR mutation with respect to PFS (P < .001).[36]
    5. OS was similar for gefitinib and carboplatin/paclitaxel, with no significant difference between treatments overall (HR, 0.90; 95% CI, 0.79–1.02; P = .109) or in EGFR mutation–positive (HR, 1.00; 95% CI, 0.76– 1.33; P = .990) or EGFR mutation–negative (HR, 1.18; 95% CI, 0.86–1.63; P = .309; treatment by EGFR mutation interaction P = .480) subgroups. A high proportion (64.3%) of EGFR mutation–positive patients randomly assigned to carboplatin/paclitaxel received subsequent EGFR tyrosine kinase inhibitors. PFS was significantly longer with gefitinib for patients whose tumors had both high EGFR gene copy number and EGFR mutation (HR, 0.48; 95% CI, 0.34–0.67) but significantly shorter when high EGFR gene copy number was not accompanied by EGFR mutation (HR, 3.85; 95% CI, 2.09–7.09).
  2. Two phase III trials from Japan prospectively confirmed that patients with NSCLC and EGFR mutations have improved PFS but not OS when treated with gefitinib.[37,38]
    1. In the first trial, 230 chemotherapy-na´ve patients with metastatic, NSCLC, and EGFR mutations were randomly assigned to receive gefitinib or carboplatin-paclitaxel.[37]
      • In the planned interim analysis of data for the first 200 patients, PFS was significantly longer in the gefitinib group than in the standard-chemotherapy group (hazard ratio for death or disease progression with gefitinib, 0.36; P < .001), resulting in early termination of the study.
      • The gefitinib group had a significantly longer median PFS (10.8 months vs. 5.4 months in the chemotherapy group; HR, 0.30; 95% CI, 0.22–0.41; P < .001).[37][Level of evidence: 1iiDiii] The median OS was 30.5 months in the gefitinib group and 23.6 months in the chemotherapy group (P = .31).
    2. In the second trial, the West Japanese Oncology Group conducted a phase 3 study (WJTOG3405) in 177 chemotherapy-na´ve patients aged 75 years or younger and diagnosed with stage IIIB/IV NSCLC or postoperative recurrence harboring EGFR mutations (either the exon 19 deletion or L858R point mutation).[38]
      • Patients were randomly assigned to receive either gefitinib or cisplatin plus docetaxel (administered every 21 days for three to six cycles). The primary endpoint was PFS.
      • The gefitinib group had significantly longer PFS compared with the cisplatin plus docetaxel group, with a median PFS time of 9.2 months (95% CI, 8.0–13.9) versus 6.3 months (5.8–7.8; HR, 0.489; 95% CI, 0.336–0.710, log-rank, P < .0001).[38][Level of evidence: 1iiDiii]
  3. Similar benefit may be achieved with erlotinib.
    1. In an open-label, randomized, phase III trial (NCT00874419) from China, 165 patients older than 18 years with histologically confirmed stage IIIB or IV NSCLC and a confirmed activating mutation of EGFR (exon 19 deletion or exon 21 L858R point mutation) received either oral erlotinib (150 mg/day) until they experienced disease progression or unacceptable toxic effects, or up to four cycles of gemcitabine plus carboplatin.[39]
      • Median PFS was significantly longer in erlotinib-treated patients than in those treated with chemotherapy (13.1 [95% CI, 10.58–16.53] vs. 4.6 [4.21–5.42] months; HR, 0.16; 95% CI, 0.10–0.26; P < .0001).[39][Level of evidence: 1iiDiii]

The above trials demonstrated that EGFR tyrosine kinase inhibitors such as gefitinib or erlotinib are superior to the platinum combination chemotherapy as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia. It is likely that these results are applicable to non-Asian populations.

  1. In a European study (EURTAC), 1,227 patients with advanced NSCLC were screened for EGFR mutations. Of these, 174 patients with EGFR mutations were randomly assigned to receive erlotinib or platinum-based chemotherapy.[40] The primary endpoint was PFS.
    • In an interim analysis of the first 153 patients, PFS in the chemotherapy arm was 5.2 months (95% CI, 4.5–5.8) compared to 9.7 months (95% CI, 8.4–12.3) in the erlotinib arm (HR, 0.37; P < .0001). Median survival was 19.3 months in the chemotherapy arm and 19.5 months in the erlotinib arm (HR, 0.80; P = .42).[41][Level of evidence: 1iiDiii]

Maintenance therapy following first-line chemotherapy

One treatment strategy that has been investigated extensively in NSCLC is maintenance therapy following initial response to chemotherapy. Options for maintenance therapy that have been investigated include the following:

  • Continuing the initial combination chemotherapy regimen.
  • Continuing only single-agent chemotherapy.
  • Introducing a new agent as "maintenance."

Multiple randomized trials have evaluated the efficacy of continuing first-line combination cytotoxic chemotherapy beyond three to four cycles.

Evidence (maintenance therapy following first-line chemotherapy):

  1. None of the trials of continued cytotoxic combinations showed a significant OS advantage with additional or longer durations beyond four cycles.
  2. Three trials found statistically significantly improved PFS or time to progression with additional chemotherapy.[42,43,44]
  3. No consistent improvement in quality of life was reported.[43,45,46]
  4. Chemotherapy-related toxicities were greater with prolonged chemotherapy.[45,46]

These data suggest that PFS, but not OS, may be improved either by continuing an effective chemotherapy beyond four cycles or by immediate initiation of alternative chemotherapy. The improvement in PFS, however, is tempered by an increase in adverse events from additional cytotoxic chemotherapy and no consistent improvement in quality of life. For patients who have stable disease or who respond to first-line therapy, evidence does not support the continuation of cytotoxic chemotherapy until disease progression or the initiation of a different chemotherapy prior to disease progression. Collectively, these trials suggest that first-line cytotoxic combination chemotherapy should be stopped at disease progression or after four cycles in patients whose disease is not responding to treatment; it can be administered for no more than six cycles.[42,43,45,46]

Evidence (first-line platinum-based combination chemotherapy followed by pemetrexed):

  1. The findings of two randomized trials (NCT00102804 and NCT00789373) have shown outcomes with the addition of pemetrexed following standard first-line platinum-based combination chemotherapy.[44,47]
    1. In the first trial, 663 patients with stage IIIB or stage IV disease who had not progressed on four cycles of nonpemetrexed platinum-based chemotherapy were randomly assigned (2:1 ratio) to receive pemetrexed or placebo until disease progression.[47]
      • Both the primary endpoint of PFS and the secondary endpoint of OS were statistically significantly prolonged with the addition of maintenance pemetrexed (median PFS, 4.3 months vs. 2.6 months; HR, 0.50; 95% CI, 0.42–0.61; P < .0001; median OS, 13.4 months vs. 10.6 months; HR, 0.79; 95% CI, 0.65–0.95; P = .012).
      • Benefit was not seen in patients with squamous histology.
      • Higher than grade 3 toxicity and treatment discontinuations resulting from drug-related toxic effects were higher in the pemetrexed group than in the placebo group.
      • No pemetrexed-related deaths occurred.
      • Relatively fewer patients in the pemetrexed group than in the placebo group received systemic post-discontinuation therapy (227 [51%] vs. 149 [67%]; P = .0001).
      • Quality of life during maintenance therapy with pemetrexed was similar to placebo, except for a small increase in loss of appetite and significantly delayed worsening of pain and hemoptysis as assessed using the Lung Cancer Symptom Scale.[48] The quality-of-life results should be evaluated with caution as there was a high degree of censoring (> 50%) for the primary quality-of-life endpoint of time to worsening of symptoms.
      • Trials have not evaluated maintenance pemetrexed versus pemetrexed at progression.
    2. In the second trial, 539 patients with NSCLC with nonprogression following treatment with pemetrexed and cisplatin were randomly assigned to continued pemetrexed or placebo.[44]
      • There was a statistically significant improvement in the primary endpoint of PFS (4.1 months vs. 2.8 months (HR, 0.62; 95% CI, 0.49–0.79) but no improvement in OS.[44][Level of evidence: 1iDiii]

Evidence (maintenance erlotinib following platinum-based doublet chemotherapy):

  1. One trial (NCT00556712) reported favorable outcomes with maintenance erlotinib after four cycles of platinum-based doublet chemotherapy in patients with stable disease.[49]
    1. In this trial, 889 patients with NSCLC but without progressive disease were randomly assigned to receive erlotinib (150 mg/day) or placebo until they experienced progressive disease or unacceptable toxicity.[49]
      • Median PFS was significantly longer with erlotinib than with placebo: 12.3 weeks for patients in the erlotinib group versus 11.1 weeks for those in the placebo group (HR, 0.71; 95% CI, 0.62–0.82; P < .0001).
      • In the overall population, patients whose tumors had activating EGFR mutations derived the greatest PFS benefit from maintenance erlotinib treatment (n = 49; HR, 0.10; P < .0001).
      • Patients whose tumors with wild-type EGFR also obtained significant PFS and OS improvements (HR, 0.78 and 0.77, respectively).
      • In the subgroup of patients with stable disease whose tumors did not have activating EGFR mutations (n = 217), both PFS and OS were significantly prolonged with erlotinib (HR, 0.72; 95% CI, 0.54–0.96; P = .0231 and HR, 0.65; 95% CI, 0.48–0.87; P = .0041, respectively).
      • In patients whose tumors had activating EGFR mutations (n = 30), OS was also improved with erlotinib (HR, 0.48; 95% CI, 0.14–1.62) but was not statistically significant in this analysis.[50]
      • EGFR IHC [immunohistochemistry], EGFR FISH [fluorescence in situ hybridization], KRAS mutation, and EGFR CA-SSR1 [simple sequence repeat 1] repeat length status were not predictive for erlotinib efficacy.[51]KRAS mutation status was a significant, negative prognostic factor for PFS.[51][Level of evidence: 1iDiii]

Radiation therapy

Radiation therapy may be effective in palliating symptomatic patients with local involvement of NSCLC with any of the following:

  • Tracheal, esophageal, or bronchial compression.
  • Pain.
  • Vocal cord paralysis.
  • Hemoptysis.
  • Superior vena cava syndrome.

In some cases, endobronchial laser therapy and/or brachytherapy have been used to alleviate proximal obstructing lesions.[1]

Although EBRT is frequently prescribed for symptom palliation, there is no consensus on which fractionation scheme should be used. Although different multifraction regimens appear to provide similar symptom relief,[52,53,54,55,56,57] single-fraction radiation may be insufficient for symptom relief compared with hypofractionated or standard regimens, as evidenced in the NCT00003685 trial.[2][Level of evidence: 1iiC] Evidence of a modest increase in survival in patients with a better PS given high-dose radiation therapy is available.[4,58][Level of evidence: 1iiA] In closely observed asymptomatic patients, treatment may often be appropriately deferred until symptoms or signs of a progressive tumor develop.

Evidence (radiation therapy):

  1. A systematic review identified six randomized trials of high-dose rate brachytherapy (HDREB) alone or with EBRT or laser therapy.[59]
    • Better overall symptom palliation and fewer re-treatments were required in previously untreated patients using EBRT alone.[59][Level of evidence: 1iiC]
    • HDREB provided palliation of symptomatic patients with recurrent endobronchial obstruction previously treated by EBRT, when it was technically feasible.

Treatment Options Under Clinical Evaluation

Treatment options under clinical evaluation include the following:

  1. New chemotherapy regimens.
  2. Other systemic agents.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.


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