Non-Small Cell Lung Cancer Treatment & Management

The roles of surgery, chemotherapy, and radiation therapy for non-small cell lung cancer (NSCLC) are discussed in this section (see the table below). Because most lung cancers cannot be cured with currently available therapeutic modalities, the appropriate application of skilled palliative care is an important part of the treatment of patients with NSCLC.

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.

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.

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 ears, nose, and throat 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 location. 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.

Preoperative evaluation

Preoperative evaluation should include a careful assessment of resectability, cardiopulmonary reserve, and perioperative risk.

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. With an FEV₁ of less than 1 L, patients are not considered candidates for surgery. These factors are further modified by the presence of cardiac disease or other comorbid conditions.

High-resolution CT and PET scanning are helpful in preoperative planning of surgery in early stage lung cancer.^[44]

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.^[45] Retrospective data (SEER) show lobectomy and segmentectomy have similar survival among patients with small lung cancer (< 1 cm).^[46] 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%.^[47]

A retrospective SEER analysis showed no difference in overall survival in patients older than 74 years. However, smaller single-institution studies show good long-term survival in stage I patients treated with sublobar approaches. 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.^[48]

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.^[49] 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.^{[50, 51]}

Mediastinal lymphadenectomy

The role of routine mediastinal lymphadenectomy versus lymph node sampling remains controversial. A large randomized trial comparing these modalities for patients with N0 or hilar N1 disease is still in progress. The authors 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.^[52]

Postoperative evaluation

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.^[53] 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.

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

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.^[54] Radiation is a reasonable option for lung cancer treatment among those who are not candidates for surgery.^[55]

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).^[56]

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.^[57] The study found that female sex, lower Karnofsky performance score (KPS), less pronounced weight loss, squamous history, 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.

Other techniques for nonoperative treatment for early-stage lung cancers include stereotactic body radiotherapy (SBRT) that uses precise targeting of high-dose radiation to the tumor, typically in 1-2 fractions, while minimizing toxicity to normal tissues.

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%.^[58] This is being studied in a randomized fashion by the Radiation Therapy Oncology Group (RTOG). 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.

A nonrandomized study by Grills et al comparing 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 found that, compared with surgery, SBRT was associated with shorter overall survival but similar recurrence rates and cause-specific mortality.^[59]

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.^[60]

The role of adjuvant radiation therapy after resection of the primary tumor remains controversial.^{[61, 62]} 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 48%).

This finding has not been replicated; hence, at this time, postoperative radiation therapy for stage I and II lung cancer is reserved for positive margins, until further trials are conducted with modern radiation therapy planning and delivery.

In an observational cohort study of patients aged 65 years or older, adjuvant chemotherapy did have a similar benefit compared with younger patients. However, a subset analysis of patients aged 80 years or older suggests adjuvant chemotherapy might have more adverse effects in this population.^[63]

Megavoltage cinema images are helpful in treating small lesions and help prevent intrathoracic movement changes during radiation.^[64]

Only 30-35% of patients with NSCLC present with sufficiently localized disease at diagnosis to attempt curative surgical resection (stages IA and IB, IIA and IIB, and IIIA). 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. The relapse rate after surgical resection of localized NSCLC is high. Recent trials have shown a survival benefit with adjuvant chemotherapy (ie, chemotherapy given after surgery) in resected stage IIA, IIB, and IIIA NSCLC.^{[65, 66]}

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. In 2011, the NCCN discussed the debate but did not reach a recommendation because the evidence is unclear.^[38]

In advanced NSCLC, patients with good performance status (ie, 0-2 on the Zubrod or Eastern Cooperative Oncology Group [ECOG] scale), greater than 70% on the Karnofsky scale (see the table below), and less than 10% body weight loss are good candidates for chemotherapy.

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.^{[67, 68]}

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%.

Multiple randomized, controlled trials and large meta-analyses all confirm the superiority of combination chemotherapy regimens up front for advanced NSCLC. Two-drug combinations showed better response rate (26% vs 13%) as well as improved 1-year survival (35% vs 30%). Addition of a third cytotoxic drug increased toxicity with a modest improvement in response rate, but no survival benefit.^[69] Hence, most first-line patients should be offered a chemotherapy doublet.

Cisplatin has been the cornerstone of most combination regimens studied in advanced NSCLC.^[70] 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.^[71]

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.

The cisplatin-gemcitabine did appear to have an increased progression free survival, compared to 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 to nongemcitabine combinations. This effect was not sustained when compared against other third-generation cisplatin combinations.^[72]

For some time, NSCLC histology was thought to not impact chemotherapy responsiveness. A phase III trial comparing upfront cisplatin-pemetrexed to 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, patients with nonsquamous histology had a statistically better median survival with the cisplatin-pemetrexed combination: for adenocarcinoma (12.6 vs 10.9 mo) and large cell histology (10.4 vs 6.7 mo). 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.^[73]

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.

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.^[74]

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.^[75]

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 mRNA 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.^[76]

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.

A randomized, controlled, 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.^[77]

Complications

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

• Febrile neutropenia or bleeding may result from bone marrow suppression.
• Hyponatremia or hypomagnesemia may result from cisplatin nephrotoxicity.
• Renal failure or ototoxicity may result from cisplatin.
• Peripheral neuropathy may result from cisplatin, paclitaxel, and vinorelbine.

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 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.^{[78, 79]}

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.^{[80, 81]} An RTOG study 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).^{[82, 83, 84]}

Chemotherapy regimens that have been studied in combination with radiation therapy include cisplatin/vinblastine and cisplatin/etoposide (5-y survival of 15%).^[80] 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.^{[85, 86, 87]}

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.^[88]

The high locoregional failure rate with chemoradiation alone has led to study of chemoradiation followed by surgical resection.^{[65, 62, 89]} 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 NSLSC, neoadjuvant chemoradiation followed by surgery led to better survival.^[90]

With the increased understanding of molecular abnormalities in lung cancer, recent 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 NSLSC. However, the likelihood of a mutation depends on the histologic subtype of the cancer. The 2011 NCCN guidelines emphasize that histologic testing should precede mutation testing.^[38]

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.

Gefitinib represents a class of EGFR tyrosine kinase inhibitors (TKIs) that act intracellularly to block activation of the EGFR pathway.^{[91, 92]} Two large phase II trials led to the expedited 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) as compared to placebo.^[92]

The INTEREST trial studied gefitinib in comparison to docetaxel in the second-line setting, which showed no significant difference in survival (7.6 vs 8 mo). Based on these data, gefitinib is no longer available in the United States to new patients. Under the Iressa Access Program, gefitinib will be available to a limited patient population in the United States. 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). Patients who were positive for the EGFR gene mutation had significantly longer progression-free survival in the gefitinib group compared with those who received carboplatin-paclitaxel. Conversely, patients who were negative for the mutation had significantly longer progression-free survival in the carboplatin-paclitaxel group.^[93]

In the IPASS study, EGFR mutation was found to be the strongest predictor of progression-free survival and response to gefitinib.^[94]

A second EGFR TKI, erlotinib, improved survival rates compared to placebo in the second- and third-line setting.^{[95, 96]} Erlotinib demonstrated improved response rates (8% vs < 1%), and overall survival (6.7 vs 4.6 mo). This led to the FDA approval of erlotinib in the second-line setting. The 2011 NCCN guidelines recommend erlotinib as a first-line therapy in patients with any of 3 histologies (adenocarcinoma, large cell carcinoma, and NSCLC not otherwise specified) and a positive EGFR mutation.^[38]

In an optimal trial of patients with adenocarcinoma of the lung with EGFR mutation, erlotinib was found to improve progression-free surival compared with chemotherapy (13.1 mo vs 4.6 mo).^[97]

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.

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.^[98]

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 with gefitinib or erlotinib.^[99] The 2011 NCCN guidelines add that EGFR mutations are present in adenocarcinomas in approximately 10% of Western patients and 50% of Asian patients.^[38]

Cetuximab, a monoclonal antibody that binds the EGFR receptor, is used in colorectal cancer as well as squamous cell cancer (SCC) of the head and neck. It was studied in the first-line setting, in combination with cisplatin-vinorelbine, compared to cisplatin-vinorelbine alone, in patients with NSCLC that expressed EGFR by immunohistochemistry.^[100]

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. K-ras mutations have been shown to demonstrate resistance to cetuximab in colon cancer, and this probably holds true for non-small cell lung cancer as well. The 2011 NCCN guidelines support this conclusion by noting that K-ras mutations are resistant to gefitinib and erlotinib. Clinicians are encouraged to order both EGFR and K-ras testing. However, if the EGFR mutation is present, echinoderm microtubule-associated protein-like 4 (EML4) testing is not necessary, as the EGFR and EML4 mutations are mostly mutually exclusive.^[38]

A randomized, double-blind, phase III trial assessed the use of vandetanib, a once-daily oral inhibitor of vascular EGFR and EGFR signaling.^[101] 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.

Further studies on these molecular markers are ongoing and are awaited to determine optimal strategies for the use of these agents.

An ECOG study has shown that addition of an anti-angiogenesis agent bevacizumab (Avastin) to standard first-line carboplatin-paclitaxel resulted in significant prolongation of survival. The 2011 NCCN guidelines support this therapy.^[38] 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 now been approved for use in this setting in combination with chemotherapy.^[102]

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%) with modest improvement in progression-free survival (6.7 vs 6.1 mo).Overall survival was not different.^[103]

In a phase II trial, Karp et al studied the effect of combined anti-insulinlike growth factor 1 receptor antibody CP-751,871 (figitumumab) 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 10-20 mg/kg (ie, PCI(10), PCI(20)) or paclitaxel and carboplatin alone (PC) every 3 weeks for up to 6 cycles.

In this phase II trial, PCI(20)/PC hazard ratio for progression-free survival was 0.8-0.56, concluding PCI(20) to be safe and effective in NSCLC. A randomized, open-label, phase III trial is currently under way.^[104]

Crizotinib (Xalkori) was approved by the US Food and Drug Administration 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 (by Abbott Molecular). Approval was based on 2 multicenter trials (n=255). Median response duration for the trials ranged from 41.9-48.1 weeks.^[105]

Stage IA/IB (T1aN0M0 , T1bN0M0, T2aN0M0)

Surgery is the treatment of choice for stage I NSCLC. A careful preoperative assessment of residual pulmonary reserve should be carried out prior to surgical planning. Although lobectomy is generally considered to be optimum procedure, those with limited pulmonary reserve may be considered for more limited resection 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.

VATS may be used for surgical resection, given the 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 radio frequency 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 that with 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.^[106] 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.^[107]

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.

A 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 4 cycles of platinum-based adjuvant chemotherapy.

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

The management of stage IIIA NSCLC is quite controversial, and 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%. Stage IIIA has been an area of active research due to poor long-term result because of low resectability rates and very few patients (5-10%) who achieve long-term benefit with radiation therapy alone.

Patients who have mediastinal nodes involved with NSCLC (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. 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. There does not appear to be significant survival benefit for further chemotherapy or surgery in patients treated upfront with chemoradiation.

A large randomized trial conducted by EORTC compared surgery versus radiation therapy following neoadjuvant chemotherapy and found no significant difference between the 2 approaches in stage IIIA N2 disease. Neoadjuvant chemotherapy followed by surgery may, however, be considered for younger patients with good performance status with stage IIIA disease.

Patients with stage III (T3-4, N1) disease of the superior sulcus are usually treated with neoadjuvant chemotherapy followed by surgical resection, since 2-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 those with involved mediastinal nodes. Prospective trials also have revealed similar results and have been conflicting with regard to reduction in local recurrence with postoperative radiation therapy. A meta-analysis of 9 randomized trials of postoperative radiation therapy did not result in survival benefit in the entire group as well as 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.^[108] 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.^[109]

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 statistical significant improvement for progression-free survival or overall survival; however, significant improvement was shown in overall response rate.^[110]

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.^[111]

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 to chemotherapy followed by radiation therapy.

Patients with stage IIIB NSCLC and poor performance status are not good candidates for chemotherapy or 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.

Patients with isolated synchronous nodules (either in same or opposite lung) should be treated as 2 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, and no therapeutic advantage is obtained with the use of 3 drugs.

Updated guidelines from ASCO recommend stopping first-line cytotoxic chemotherapy at disease progression or after 4 cycles in patients who are not responding to treatment, and stopping 2-drug cytotoxic chemotherapy at 6 cycles, even in patients who are responding to therapy.^[112]

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 4 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.^[113]

Small-molecule EGFR TKIs such as gefitinib and erlotinib may benefit nonsmokers with adenocarcinomas, particularly bronchoalveolar carcinoma, especially those females of Asian origin. 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. 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 non-small cell lung cancer 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 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.

The 2009 update to the American Society of Clinical Oncology (ASCO) guidelines on chemotherapy for stage IV disease includes the following recommendations for treatment^[112] :

• A platinum-based combination of 2 cytotoxic drugs for patients performing at status 0 to 1
• A single cytotoxic drug for patients performing at status 2
• A halt to chemotherapy if the patient does not respond, if the disease progresses, or if 6 cycles have been administered
• Gefitinib for patients with the EGFR mutation
• Cytotoxic chemotherapy for patients without the EGFR mutation
• Bevacizumab should be administered with carboplatin-paclitaxel in most circumstances
• Cetuximab with cisplatin-vinorelbine for patients who are EGFR positive by immunohistochemistry
• Second-line therapy: docetaxel, erlotinib, gefitinib, or pemetrexed
• Third-line therapy: erlotinib, provided neither erlotinib or gefitinib have been administered previously

The 2009 ASCO guideline states that the available data on third-line use of cytotoxic drugs and determining treatment from molecular markers are insufficient to form conclusions.^[112]

The 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.

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).

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.^[114]

Combining nicotine replacement, bupropion, and social or behavioral support can increase the quit rate to 35%.^[115]

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 nonsteroidal anti-inflammatory drugs (NSAIDs) effect of lower colorectal and adenoma incidence.^[116]

Screening

No established role exists at this time for screening modalities for NSCLC. Prevention is the more effective modality for decreasing the prevalence of NSCLC. Current modalities including chest radiography, chest computed tomography (CT), and sputum cytology has been studied. (See Workup.) While both chest radiography and CT scanning have the potential to pick up early lung cancer, they have not been proven to decrease cancer-specific mortality.

The controversial I-ELCAP study was an observational cohort study that showed that lung cancers could be diagnosed at an early stage with protocol-based CT screening, but this study had no control group to determine the mortality benefits of such an approach. The authors’ conflicts of interest have also caused the findings of this study to be questioned.

In a randomized study, low-dose CT screening improved survival in patients; however, many false positive results were still noted.^[117]

A large National Cancer Institute (NCI)-sponsored national lung cancer screening trial is ongoing to evaluate screening CTs as compared to screening chest radiographs.^[118]

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

Ear, nose, and throat; general; orthopedic; vascular; and/or neurosurgical or neurological services may also be required to address complications caused by spread of the disease.

Inpatient treatment should be tailored to the specific presenting problem.

Surgery is the treatment of choice for patients with NSCLC stages I through IIIA.^[5] In addition, patients with resected lung cancer have a high risk of relapse and are treated with adjuvant chemotherapy.^[119] Patients with stage IIIB and IV NSCLC are usually offered chemotherapy with the option of surgery.

Speak directly with the patient’s personal physician to suggest prompt follow-up for the patient thought to have new-onset lung cancer.

Schedule follow-up clinical appointments for patients who do not have primary care physicians.