Non-Small-Cell Lung Cancer

Treatment

In operable candidates, clinically staged IA, IB, IIA, and IIB NSCLC should undergo anatomic complete surgical resection. Primarily, patients with stages IIIB and IV disease are treated nonoperatively. Although multimodality therapy is routinely recommended for stage IIIA disease, it is recommended that it be performed within a clinical trial.

Surgical Approach

Over the past two decades, the new subspecialty of general thoracic surgery has evolved in the United States. Surgeons in this specialty have completed their cardiothoracic surgery training and have obtained further subspecialty training in malignant and benign diseases of the chest.

The appropriate surgical treatment of NSCLC is resection of the lobe containing the tumor to achieve a negative surgical margin (R0), 16 to 20 lymph nodes pathologically assessed from at least 3 lymph node stations (2 from the ipsilateral and contralateral mediastinum), and a pleural wash of the affected side. Tumor spillage is avoided. Occasionally, a bilobectomy or pneumonectomy is required. Mortality approximates 3% following lobectomy and 7% following pneumonectomy. For peripheral lesions smaller than 3 cm with AIS or MIA, wedge resection with negative margins provides excellent long-term survival. For central lesions or lesions larger than 2 cm, a wedge or segmental resection is associated with a three- to five-times-higher incidence of local recurrence and a lower 5-year survival rate than a lobectomy. Therefore, if the patient can tolerate the procedure, the standard operation should be a lobectomy, rather than a wedge resection or segmentectomy. As a curative resection, segmentectomy has not been sufficiently evaluated, and more recent investigation suggests that in select tumors, when the bronchus and vascular supply are individually ligated with a regional node resection, survival appears to be comparable and it salvages lung parenchyma.

A retrospective evaluation based on the Surveillance, Epidemiology, and End Results (SEER) database found that in stage I lung cancer, the difference in long-term survival between a wedge resection and lobectomy was negligible after 71 years of age.

A radiologic and PET evaluation has demonstrated that patients with lesions smaller than 2 cm, peripheral ground-glass opacity with a PET maximum SUV of less than 2.5, and no evidence of metastatic disease may be considered for a more limited resection if the surgical margin is approximately the size of the lesion. A prospective randomized clinical trial (CALGB 140503; clinicaltrials.gov NCT00499330) is accruing patients to assess whether anatomic lobectomy provides superior survival compared with sublobar resection in peripheral stage I NSCLC lesions smaller than 2 cm.

VATS

Traditionally, lung cancers have been resected through a posterolateral thoracotomy incision. Muscle-sparing incisions may reduce pain. The current trend is toward an even less invasive approach: lobectomy and lymph node dissection with VATS. This approach appears to offer the same cancer operation and survival with perhaps lower morbidity.

Two VATS methods have been described: the mass hilar ligation technique and individual ligation of the vasculature and airway. Patients with peripheral tumors up to 4 to 6 cm without clinical hilar or mediastinal adenopathy appear to be good candidates for a VATS procedure. Conversion rates to open thoracotomy are 10%, and hospital stays are usually 3 to 5 days.

The results of several VATS series show lower complication rates than for reported series for thoracotomy; granted, a selection bias may have occurred. One small randomized trial showed a significant benefit favoring VATS. Patients have better shoulder function, better performance on the 6-minute walk, and less impairment of vital capacity after VATS than after thoracotomy. A VATS approach may be better tolerated than other approaches for older patients.

Patients with pathologic stage IA disease have a 70% to 80% 5-year survival rate after resection, whereas 5-year survival rates are 60% in those with stage IB disease and 40% to 50% in those with stage IIA/IIB disease. Patients found to have N2 (stage IIIA) disease located at a single nodal level have a 25% to 30% 5-year survival rate.

Mediastinal lymph node involvement

The standard lung cancer operation should include sampling or dissection of mediastinal lymph nodes. The presence of metastases in any of the mediastinal lymph nodes (N2 and/or N3 disease) is indicative of advanced disease and is thought by some to represent a contraindication to surgery. Resection of mediastinal disease may have prognostic significance, implications for postoperative care, and potential therapeutic value. Some series of patients with N2 disease have shown a 5-year survival rate of 20% to 30%, but patients in these series are highly selected.

Patients with N2 disease may potentially benefit from neoadjuvant treatment. Patients with N3 disease are considered to be stage IIIB and less likely to benefit from surgical resection. A few retrospective reports have demonstrated survival from induction therapy in patients with microscopic N3 involvement. The American College of Surgeons has completed accrual to a randomized, prospective study comparing survival following mediastinal lymph node sampling vs dissection. Complications and operative mortality appear equivalent between the sampling and dissection groups. Long-term survival is under investigation. Also, clinical trials are currently testing preoperative chemotherapy and chemoradiation therapy in patients with mediastinal node involvement.

Preoperative histologic assessment of the mediastinal lymph nodes is essential if multilevel metastases are suspected, because there have been few long-term survivors among patients with metastatic disease at more than one level. Nonsurgical treatment appears preferable, or patients should be offered participation in a trial designed to assess the benefits of neoadjuvant therapy. Although patients with stage IIIB tumors are usually treated with irradiation and chemotherapy (see later discussions), the occasional patient with isolated involvement of the vena cava or atrium can undergo resection.

Carcinoid tumors

Although the majority of carcinoid tumors remain localized, regional lymph node metastases are identified in 5% to 10% of patients. The surgical approach, therefore, should be similar to that used in NSCLC. If a small tumor in a proximal airway is identified and there is no histologic evidence of lymph node disease, a bronchoplastic procedure with preservation of lung tissue can sometimes be performed. Rates of survival at 10 years are greater than 90% for patients with stage I disease and 60% for patients with stage II disease.

Adjuvant Therapy

Chemotherapy

Classic postoperative adjuvant chemotherapy has been tested in three randomized trials conducted by the Lung Cancer Study Group (LCSG). For almost 20 years, the relative value of adjuvant chemotherapy for resectable NSCLC has been disputed and debated. A randomized prospective study involving 488 patients (Keller et al: N Engl J Med 2000) showed no benefit to adjuvant chemotherapy. The ALPI (Adjuvant Lung Project Italy) study of 1,209 patients also showed no survival benefit. In contrast, the IALT (International Adjuvant Cancer Trial) randomized 1,867 patients to receive cisplatin(Drug information on cisplatin)-based adjuvant chemotherapy or no treatment. At 5 years, the treatment arm showed a survival advantage of 4.1% (P = .003), compared with the observation arm. However, that benefit appeared to diminish with longer follow-up. With 3 additional years of follow-up, there was a significant difference between the results of overall survival before and after 5 years (HR = 0.86; P = .01 vs HR = 1.45; P = .04). Similar results were observed with disease-free survival and confirmed the efficacy of chemotherapy for the first 5 years after surgery; however, they suggested possible late adjuvant chemotherapy-related mortality and underscored the need for long-term follow-up of adjuvant lung cancer trials.

Two trials, the Canadian JBR-10 and CALGB 9633, both demonstrated initial clinically significant improvement in survival, with minimal chemotherapy side effects; cisplatin and vinorelbine were used in the BR-10 trial and carboplatin(Drug information on carboplatin) and paclitaxel(Drug information on paclitaxel) were used in CALGB 9633. These results, in combination with the recent positive findings of the adjuvant trial of UFT (a drug composed of tegafur(Drug information on tegafur) and uracil mixed at a 1:4 ratio) in patients with stage IB NSCLC, increase the likelihood of adjuvant platinum-based therapy becoming the standard of treatment for patients with stages IB-IIIB NSCLC. Recent results of a prospective phase III trial from the Spanish Lung Cancer Group (SLCG) NATCH trial (Neoadjuvant Taxol Carboplatin Hope) compared the use of adjuvant and neoadjuvant and surgery alone in 616 patients with stages I (> 2 cm), II, and T3 N1. For those who received chemotherapy, three 3-week cycles of paclitaxel (200 mg/m²) and carboplatin (at an AUC of 6) were given. Despite an excellent safety profile, a major radiologic response at 59%, and a complete response of 9% of induction patients, there was no difference found in survival. Again, it appears that the survival advantage in the treatment arm was lost, except in patients with larger primary tumors (> 4 cm) or more advanced disease (stage IIIA).

A meta-analysis by the Lung Adjuvant Cisplatin Evaluation (LACE) group found that in completely resected NSCLC patients, the 5-year overall survival benefit of cisplatin-containing adjuvant regimens was 5.4% (HR = 0.89; P = .004). There appeared to be a survival advantage of 8.9% for cisplatin-vinorelbine, which was superior to other regimens containing cisplatin. The greatest benefit of adjuvant therapy was seen in patients having disease of a higher stage (14.7% for stage III, 11.6% for stage II, 1.8% for stage I; Douillard JY et al: J Clin Oncol 2010).

Based on these results from adjuvant chemotherapy trials, the initial enthusiasm has been somewhat tempered. The potential benefits are higher efficacy of chemotherapy early in the natural history of disease, facilitation of subsequent local therapy, and early eradication of distant micrometastases. Further investigation in the use of adjuvant therapy is under way to determine which patients will benefit and what is the optimal treatment.

Stage I disease. Currently approved chemotherapeutic regimens do not appear to provide any survival benefit in the stage IA patient population and are not advised outside of the clinical trial setting. From the subset analysis of CALGB 9335, patients with stage IB tumors larger than 4 cm may have some benefit, given the likelihood for recurrence. Currently under investigation is the use of tumor histology and marker evaluation to select the appropriate patient and the ideal chemotherapeutic plan with the greatest efficacy and least toxicity.

JBR.10, however, which included 532 patients with stage IB or II completely resected cancers who were randomized to cisplatin/vinorelbine or observation, demonstrated that the survival benefit appears to be confined to N1 patients over 9 years of prolonged follow-up.

The current trend is to provide involvement in a chemopreventive clinical trial for patients with stage IA disease. For patients with stage IB disease, particularly those with tumors larger than 4 cm in diameter, platinum-based adjuvant chemotherapy (cisplatin or carboplatin combined with a taxane or vinorelbine) or involvement in an adjuvant therapy clinical trial should be strongly considered.

Stage II/III disease. In two trials, postoperative adjuvant chemotherapy with six courses of CAP (cyclophosphamide, Adriamycin [doxorubicin], and Platinol [cisplatin]), given alone in one study and following postoperative radiation therapy in the other, resulted in a modest improvement in median survival but had no impact on long-term survival. In contrast, the IALT, ANITA, CALGB 9623, and Canadian BR-10 trials demonstrated an initial clinically significant survival advantage, justifying consideration for adjuvant chemotherapy. In contrast to IALT, which included all resectable disease and showed a decrease in survival after 5 years, JBR.10, which included stage IB/II patients, continues to show a survival benefit with over 9 years of follow-up. While there does not appear to be a clear survival advantage to adding adjuvant mediastinal radiotherapy to chemotherapy, this is reasonable to consider when there are particularly high-risk factors for local recurrence. Potential indications for postoperative radiotherapy include:

• Mediastinal involvement

• Multiple positive lymph nodes or lymph node stations

• Extracapsular nodal extension

• Bulky nodal disease

• Grossly positive surgical margins

• Close or microscopically positive margins

Radiation therapy

A trial conducted by the LCSG showed that in patients with squamous cell carcinoma of the lungs and resected N1/N2 disease, administration of postoperative radiation therapy reduced the risk of recurrence in the chest from 20% to 1%. Although there was no improvement in overall survival, postoperative irradiation was associated with a significant improvement in disease-free survival for patients with N2 disease. A trial by the British Medical Research Council (BMRC) reached similar conclusions.

A meta-analysis of nine randomized trials assessing postoperative radiation therapy in lung cancer reported a 21% increase in mortality in patients receiving this therapy. However, many of the patients in these trials had N0 disease, for which few would advocate radiation therapy. Also, most of the patients were treated with cobalt-60 beams and technically limited treatment planning, not with modern radiation therapy techniques.

The impact of radiation therapy on survival was reanalyzed in the ANITA trial (Adjuvant Navelbine International Trialist Association), in which postoperative radiation therapy was optional, based on each center's practice. Interestingly, in patients with N2 (mediastinal) disease, adjuvant radiation therapy improved overall survival in both arms: 21% vs 17% in the observation arms and 47% vs 34% in the adjuvant chemotherapy arms (with or without radiation therapy, respectively). Based on this descriptive analysis, radiation therapy appeared to provide a benefit in addition to adjuvant chemotherapy in patients with N2 disease (whereas the converse was true in patients with N1 disease). A randomized trial with and without postoperative radiation therapy in patients with resected N2 disease is under way in Europe.

These results created a lack of consensus about treatment recommendations, with some experts advocating the use of postoperative radiation therapy to reduce local recurrence, and others avoiding it because of the absence of an effect on survival.

At present, therefore, the appropriate role of postoperative radiation therapy remains controversial. Such therapy should be seriously considered, however, in patients at high risk for locoregional relapse, in patients with resected N2 disease, or in those with other possible indications as outlined above. In patients with no known residual disease after surgery who are receiving adjuvant chemotherapy, it is reasonable to administer the chemotherapy first (because it has been associated with a survival benefit) followed by radiation therapy (for enhanced local tumor control).

Moreover, in a randomized trial (Keller et al: N Engl J Med 2000), no benefit was shown for concurrent chemoradiation therapy over radiation therapy alone in the adjuvant setting for completely resected patients with stage II/IIIA NSCLC. An exception may be in patients with microscopic residual disease (ie, positive margins or extracapsular extension), for whom a delay in radiation therapy may be detrimental.

Neoadjuvant Chemotherapy or Chemoradiation Therapy

During the past decade, numerous phase II trials showed that, in general, it is feasible to perform pulmonary resection following chemotherapy or chemoradiation therapy. Although surgery can be more difficult after preoperative treatment, morbidity and mortality are acceptable in experienced hands .

Stage IIIA/IIIB disease

The greater effectiveness of current chemotherapeutic regimens to reduce disease bulk suggested that their use before surgery, either alone or in combination with radiation therapy, might increase both resectability and survival in patients with stage IIIA NSCLC. For these patients, such an approach has been shown to be feasible; however, it is not clear whether such a strategy improves median or long-term survival over nonsurgical chemoradiotherapy .

In 2009, Albain et al reported on Intergroup 0139, a phase III study of 202 patients with stage IIIA disease that showed improved progression-free survival in the trimodality group with neoadjuvant chemoradiation followed by surgery (12.8 months vs 10.5 months; P = .017) but no difference in overall survival. The lack of survival benefit was thought to be possibly related to the high mortality rate following pneumonectomies, particularly on the right side.

Current recommendations

In select patients, preoperative treatment may have a favorable effect on outcome in surgically resectable stage IIIA NSCLC. Although aggressive neoadjuvant approaches may have increased treatment-associated mortality, in experienced institutions, potential benefits seem to outweigh the risks. The results of the Intergroup randomized trial comparing preoperative chemoradiation therapy with definitive chemoradiation therapy (in pathologic N2 disease) showed a significant improvement in progression-free survival (but not overall survival) in the surgical arm (P = .02). This approach, however, may not be optimal if a pneumonectomy is required, because this procedure was associated with a high rate of treatment-related deaths (> 20%). In a subset analysis, survival was improved for patients who underwent lobectomy, but not pneumonectomy, compared with chemotherapy plus radiation alone. In this trial, it is not clear whether patients with persistently positive N2 disease after neoadjuvant therapy will benefit from surgical resection.

Stage I-IIIA disease

Neoadjuvant chemotherapy may have a role in early-stage disease. A multicenter trial from France randomized 373 patients with stage I to IIIA NSCLC to undergo either surgery alone or chemotherapy (mitomycin [6 mg/m² on day 1], ifosfamide [1.5 g/m² on days 1 to 3], and cisplatin [30 mg/m² on days 1 to 3]) at 3-week intervals for three cycles followed by surgery. Disease-free survival was significantly longer in the patients randomized to receive neoadjuvant chemotherapy than in those treated with surgery alone (P = .02). The most striking benefit of chemotherapy was seen in patients who had minimal lymphadenopathy (either N0 or N1; P = .008). No excessive complications were seen in the chemotherapy-treated patients.

Cumulative data support a difference in treatment, but no one study is statistically significant. Pooled analyses suggest a positive benefit from neoadjuvant therapy, with all individual studies showing a trend toward improved overall survival, and significant differences in disease-free survival.

Following on previous trials was a study presented by Scagliotti in which 270 patients with stage IB-IIIA NSCLC were randomized to undergo surgery and follow-up or induction chemotherapy with cisplatin and gemcitabine (Gemzar) followed by surgery. This trial closed early because of accrual problems, after only 270 of a projected 700 patients enrolled. Overall survival trends at 3 years favored the chemotherapy plus surgery arm (P = .053). Overall survival at 3 years for the neoadjuvant arm was 67% vs 60% for surgery alone (P = .053).

A subset analysis suggested that for stage IIb-IIIa, 3-year overall survival was 70% vs 40% in favor of chemotherapy (P = .001), whereas there was no difference for patients with stage Ib-IIa who were treated. This continues to support data suggesting that for stage IIb-IIIa disease, chemotherapy, either in the adjuvant or neoadjuvant setting, provides a significant survival advantage.

Treatment of Patients With Medically Inoperable Stage I/II Disease

Some patients with resectable stage I or II NSCLC are high-risk operative candidates because of poor cardiopulmonary function or other medical problems. Other patients refuse to undergo surgery despite the recommendation of their treating physicians. In such patients, an attempt should be made to optimize pulmonary function by encouraging smoking cessation and initiating vigorous treatment, such as with bronchodilators. Evaluation by an experienced general thoracic surgeon is warranted before discounting a surgical approach. For many of these patients, stereotactic body radiation therapy (SBRT) has emerged as a safe and effective noninvasive treatment option (see discussion below).

Radiation therapy

Several institutions have reported their experience with conventional radiation therapy for such patients. Although the results are not as good as those reported in patients selected for surgery (possibly due to differences in patient selection and between clinical vs pathologic staging), patients with medically inoperable early-stage NSCLC clearly should be offered radiation therapy, with a reasonable expectation of cure. For patients with early-stage (I/II) NSCLC, surgical resection is the standard of care. However, many patients with lung cancer are not eligible for surgery because of various comorbidities. In the past, the main treatment alternative for these medically inoperable patients has been conventional radiation therapy, typically requiring once-daily treatments every weekday for approximately 7 weeks. Results with conventional radiation therapy have not been encouraging, with local tumor control rates of only 50%.

SBRT has evolved as another treatment option for patients with medically inoperable, peripheral stage I NSCLC. SBRT involves the delivery of high doses of highly precise radiation therapy in a hypofractionated scheme over three to five fractions, administering biologically equivalent doses (BEDs) greater than 100 Gy over 1 to 2 weeks, with promising local tumor control rates of 85% to 90%.

Onishi et al reported the clinical outcomes of approximately 250 patients treated in Japan with SBRT for stage I NSCLC. They reported a cumulative 5-year local tumor control rate of 84% for those treated with a BED of greater than 100 Gy vs 37% for those who received a BED of less than 100 Gy (P < .001). Interestingly, among operable patients, the 5-year overall survival rate was 72% for those treated with a BED of greater than 100 Gy vs 50% for those who received a BED of less than 100 Gy (P < .05).

Timmerman et al initally reported the results of a phase I study of SBRT in patients with medically inoperable stage I NSCLC. SBRT was delivered in three fractions over 2 weeks, with a starting dose of 800 cGy per fraction. The dose was escalated to 2,000 cGy per fraction for three fractions. Recently, Timmerman et al reported in JAMA on a phase II North American multicenter study (RTOG 0236) of 59 patients with biopsy-proven, peripheral T1-2, N0, M0 NSCLC tumors (measuring < 5 cm in diameter) and medical conditions precluding surgical treatment. Patients were treated with a total of 54 Gy in three fractions over a 1- to 2- week period, with a median follow-up of 34.4 months. The rates for disease-free survival and overall survival at 3 years were 48.3% (95% CI, 34.4%–60.8%) and 55.8% (95% CI, 41.6%–67.9%), respectively. The estimated 3-year primary tumor control was 97.6%, and the median overall survival was 48.1 months. The 2-year local control rate was excellent at 94%.

Although this treatment (ie, SBRT using three fractions of 18 to 20 Gy each) was safe and effective for patients for peripheral lung lesions, there was a significantly higher rate of grade 3 toxicity in patients with central lung lesions. Other institutional studies, such as those conducted at Henry Ford Hospital, suggest that early central NSCLC lesions can be treated safely and effectively with SBRT by using smaller fraction sizes of 10 to 12 Gy per session for three or four sessions. A prospective trial, RTOG 0813, is studying this issue further in a dose-escalation trial (clinicaltrials.gov NCT00750269).

The role of lung SBRT for operable patients is not known. A recent retrospective analysis demonstrated a promising 5-year overall survival of 51% in patients with clinical stage I operable NSCLC (with a median age of 76 years) with a 30-day post-SBRT mortality rate of 0%. Recently, an important lung cancer trial (ACOSOG Z4099/RTOG 1021) has opened, randomizing patients with high-risk stage I NSCLC to sublobar resection (with or without brachytherapy) or SBRT; results are expected in 2012-2013.

Radiofrequency Ablation

Radiofrequency ablation (RFA) is being actively studied in patients who are not operative candidates. While RFA may be an option for select patients who have peripheral lesions less than 3 cm without mediastinal disease and who are poor surgical candidates, further studies are needed with longer follow-up. Although there is considerable experience with use of RFA in patients with cancer in other organs, further evaluation of RFA and cryotherapeutic techniques for lung cancer is under way to assess complications related to the therapy (including the known risk of pneumothorax), local recurrence, and survival.

Sidebar: In a recent analysis comparing RFA with SBRT, Bilat et al reported that while survival at 1 and 3 years was similar between patient groups, the 5-year survival was higher with SBRT (47%) than with RFA (20% to 27%). Local progression rates were lower in patients treated with SBRT (4% to 15% vs 24% to 43%). Pneumothorax (19% to 63%) was the most common complication following RFA. Pneumonitis (2% to 12.5%) and chest wall pain (3% to 12%) occurred following SBRT. (Bilal H et al: Interact Cardiovasc Thorac Surg May 10, 2012 [Epub ahead of print]). In a separate study from Harvard, 55 RFAs were performed in 45 patients with stage I NSCLC. At a median follow-up of 32 months, locoregional recurrence (LRR) occurred in 21 patients (38%). Eighty percent of tumors larger than 3 cm were associated with LRR (Lanuti M et al: Ann Thorac Surg 93:921-927, 2012).

Treatment of Patients With Stage IIIA/IIIB Disease

Radiation therapy

In the past, radiation therapy was considered the standard therapy for patients with stage IIIA or IIIB disease. Long-term survival was poor, in the range of 5%, with poor local tumor control and early development of distant metastatic disease.

A randomized trial compared standard daily radiation therapy (66 Gy) with a continuous hyperfractionated accelerated radiation therapy (CHART) regimen that delivered 54 Gy over 2.5 weeks. The altered fractionation schedule resulted in improved 2-year survival.

Various efforts have assessed combining altered fractionation schema with chemotherapy. Although the results of RTOG 94-10 did not favor altered fractionation (see section on "Concurrent vs sequential chemoradiation therapy"), the long-term results of another study support this strategy.

A randomized trial of approximately 200 patients (Jeremic et al: Proc Am Soc Clin Oncol 2000) compared hyperfractionated radiation therapy (twice daily, to 69.6 Gy) and concurrent low-dose daily carboplatin/etoposide with or without weekend carboplatin/etoposide. Although investigators found no benefit with the addition of weekend carboplatin/etoposide, both arms demonstrated promising median survival times of 20 and 22 months and excellent 5-year survival rates of 20% and 23%.

Conformal radiation therapy

In the Michigan phase I dose-escalation trial of three-dimensional (3D) conformal radiation therapy for NSCLC (Hayman et al: J Clin Oncol 2001), the radiation dose was escalated based on the effective volume of irradiated lung (up to 102.9 Gy). Such doses produced acceptable toxicity and no cases of isolated failures in purposely nonirradiated, clinically uninvolved nodal regions. This strategy is now being integrated with chemotherapy.

Socinski et al reported a dose-escalation radiotherapy (from 60 Gy up to 74 Gy) trial, using 3D computer-assisted planning techniques, in patients receiving induction carboplatin and paclitaxel and concurrent weekly carboplatin/paclitaxel. Ninety-seven percent of the patients (31 of 32) completed therapy to 74 Gy, as planned. The grade 3/4 esophagitis rate overall was relatively low at 11%. Moreover, the results showed a promising median survival of 26 months and a 3-year survival of 47%. Recently, studies are exploring newer radiotherapy techniques, such as proton therapy. In one prospective study, 44 patients were treated with 74 Gy (RBE) proton therapy with weekly carboplatin/paclitaxel and had a promising median survival of 29 months. Future studies are needed to further test such new technologies.

Indeed, several analyses support the importance of radiation therapy dose escalation in stage III NSCLC. Movsas et al analyzed data from more than 1,400 patients treated in nine prospective RTOG nonoperative NSCLC studies activated during the 1990s. The analysis was stratified by the presence of chemotherapy and the accrual year. On multivariate analysis, they found that a higher BED significantly predicted for higher overall survival and higher locoregional tumor control. For an increase in BED of 10 Gy, there was a dramatic 14% reduction in the hazard of death. Similarly, researchers at the University of Michigan found a significantly improved survival in patients treated with a higher BED. To test this important hypothesis prospectively, an RTOG/Intergroup phase III trial has compared concurrent chemoradiation therapy with either 60 Gy or 74 Gy with or without cetuximab (Erbitux). However, the data monitoring committee for this study closed the high-dose arms because of a futility analysis that showed no benefit to a higher radiation dose (74 Gy vs 60 Gy) in this setting. While more details are awaited, the question regarding the role of cetuximab continues to be addressed.

Chemoradiation therapy

Chemoradiation therapy vs radiation therapy alone. At least 11 randomized trials have compared thoracic irradiation alone with chemoradiation therapy in patients with stage III NSCLC. Several meta-analyses have demonstrated a small but statistically significant improvement in survival with the combined-modality regimens.

Concurrent vs sequential chemoradiation therapy. A phase III study (Furuse et al: J Clin Oncol 1999) evaluated mitomycin, vindesine, and cisplatin (MVP), administered either concurrently or before thoracic irradiation (56 Gy), in patients with unresectable stage III NSCLC. With more than 300 patients randomized, survival favored concurrent over sequential therapy (median survival, 16.5 months vs 13.3 months, and 5-year survival rates, 15.8% vs 8.9%; P = .04). The study also reported the patterns of failure, which demonstrated a benefit of concurrent chemoradiotherapy in improving the local relapse-free survival (P = .04) but not the distant relapse-free survival (P = .6).

Curran et al presented long-term results of a larger randomized trial (> 600 patients) comparing sequential and concurrent chemoradiotherapy (RTOG 9410). The 4-year survival with concurrent cisplatin/vinblastine and once-daily irradiation was 16%, vs 10% with sequential treatment (P = .04). The result in the third treatment arm (concurrent cisplatin/oral etoposide and hyperfractionated irradiation) was intermediate, with a 4-year survival of 17%.

The role of altered radiation therapy fractionation may deserve further study. ECOG 2597 randomized patients after induction chemotherapy (with carboplatin and paclitaxel) to receive either standard radiation therapy (64 Gy/2 Gy fraction) or hyperfractionated accelerated radiation therapy, 57.6 Gy delivered as 1.5 Gy three times daily over 2.5 weeks. Although the study closed prematurely because of poor accrual (only 111 patients were eligible), the median survival in the investigational arm appeared promising (22 months).

Results of the first Patterns of Care Study (PCS) for lung cancer (Movsas et al: J Clin Oncol 2003), which was conducted to determine the national patterns of radiation therapy practice in patients treated for nonmetastatic lung cancer, were reported. As supported by clinical trials, the PCS for lung cancer demonstrated that patients with clinical stage III NSCLC received chemotherapy plus radiation therapy more than radiation therapy alone (P < .001). In clinical stage I NSCLC, though, radiation therapy alone was the primary treatment (P < .001). Factors correlating with increased use of chemotherapy included lower age (P < .001), histology (SCLC > NSCLC; P < .001), increasing clinical stage (P < .001), increasing Karnofsky performance status (P < .001), and lack of comorbidities (P = .0002) but not academic vs nonacademic facilities (P = .81). Of all patients receiving chemotherapy, approximately three-quarters received it concurrently with radiation therapy. Only 3% of all patients were treated on Institutional Review Board–approved trials, demonstrating the need for improved accrual to clinical trials. Further PCSs will be done as part of the Quality Research in Radiation Oncology (QRRO) project.

The Hoosier Oncology Group (HOG) reported the results of the phase III trial of cisplatin plus etoposide plus concurrent chest radiation therapy with or without consolidation docetaxel (Taxotere) in patients with inoperable stage III NSCLC. In a study of 203 patients (of whom 147 were randomized to receive or not receive docetaxel) with a median follow-up of 25.6 months, they reported a median survival time in the docetaxel arm of 21.6 months vs 24.2 months in the observation arm (P = .94). They concluded that consolidation docetaxel does not further improve survival, is associated with significant toxicity (including an increased rate of hospitalization and premature deaths), and should not be used in this setting.

Sidebar: Concurrent chemoradiation (CRT) has also been shown to be superior to radiation therapy alone in patients older than 70 years with unresectable stage III NSCLC. In a randomized phase III trial with 200 patients, Okamoto et al compared 60 Gy alone with the same radiation therapy plus concurrent carboplatin (30 mg/m²/d, 5 days/wk × 20 days). Survival was significantly better in the CRT arm (3-year overall survival, 35% vs 14%; P = .003). CRT using daily carboplatin is superior to radiation therapy alone for elderly patients with locally advanced NSCLC (Okamoto H et al: J Clin Oncol 30: abstract 7017, 2012).

Current treatment recommendations

At present, it is reasonable to consider concurrent chemoradiation therapy (with once-daily radiation therapy) as a treatment paradigm in stage III (inoperable) lung cancer patients with an ECOG performance status of 0/1 who have not lost more than 5% of their usual body weight. The results of a meta-analysis using individual patient data from randomized clinical trials showed that concomitant chemoradiation therapy, as compared with sequential chemotherapy and radiation therapy, improved survival of patients with locally advanced NSCLC, primarily due to a decrease in locoregional tumor progression. Overall, there was an absolute benefit in survival of 6% at 3 years.

Novel biologic agents. The results of SWOG 0023 were recently updated. This was a randomized phase III trial of gefitinib (Iressa) vs placebo maintenance after chemoradiation therapy followed by docetaxel in patients with stage III NSCLC. With a median follow-up of 27 months in 243 randomized patients, the median survival for the gefitinib arm (n = 118) was 23 months vs 35 months for the placebo arm (n = 125; P = .013). The authors concluded that in this unselected population, gefitinib did not improve survival. The decrease in survival was likely due to cancer, not to gefitinib toxicity. A secondary analysis of SWOG 0023 found that V20 (which represents the percentage of total normal lung volume that received > 20 Gy of radiation) was the greatest predictor of radiation pneumonitis. This finding is consistent with other studies showing V20 to be a reliable predictor of pneumonitis in patients who are treated with radiation therapy for lung cancer. They found that patients with a V20 of greater than 35% had a higher rate of grade 3 or higher pneumonitis than patients with a V20 of less than 35% (14% vs 6%, respectively; P = .02) and a shorter median survival (11 vs 23 months, respectively; P = .0001). Of note, there was no imbalance of the V20 parameter between the two arms of SWOG 0023. It is now considered standard for radiation oncologists to formally evaluate dose vs volume parameters in the treatment of lung cancer.

Blumenschein et al combined cetuximab with paclitaxel and carboplatin with radiation therapy. This phase II RTOG trial accrued 87 patients and reported a promising median survival of 23 months. This represents an approximately 30% increase in survival from the 17 to 18 months usually observed with chemoradiation therapy alone. This novel strategy of adding cetuximab to chemoradiation therapy in locally advanced NSCLC is being tested in a randomized phase III study (RTOG 0617). Govindan et al reported on CALGB 30407, a phase II study of pemetrexed(Drug information on pemetrexed), carboplatin, and thoracic radiation with or without cetuximab in patients with locally advanced, unresectable NSCLC. Preliminary efficacy data showed no difference in complete or partial response, median failure-free survival, or 18-month survival. Interestingly, in a small prospective study (N = 24) of poor-risk stage III NSCLC patients (SWOG 0429) who were not candidates for chemoradiation therapy, the addition of concurrent cetuximab and radiation therapy yielded a promising median survival of 14 months in this population, with minimal toxicity.

Prophylactic Cranial Irradiation

RTOG 0214 studied the role of prophylactic cranial irradiation (PCI) in patients with stage III NSCLC. The study opened in September 2002 and closed because of slow accrual in August 2007. The total accrual was 356 patients (of the targeted 1,058), of whom 340 were eligible. One-year overall survival (75.6% vs 76.9%; P = .86) and 1-year disease-free survival (56.4% vs 51.2%; P = .11) for PCI vs observation, respectively, were not significantly different. However, the incidence of CNS metastases at 1 year was 7.7% for PCI vs 18% for observation (P = .004). Thus, PCI in stage III NSCLC significantly decreases the risk of CNS metastases, with no significant difference in overall survival or disease-free survival. Moreover, PCI was associated with some decline in immediate and delayed recall at 1 year.

Treatment of Patients With Stage IV Disease

Until relatively recently, there was considerable controversy over the value of treating stage IV NSCLC patients with chemotherapy. Treatment with older cisplatin-containing regimens, such as cisplatin/etoposide, showed only a modest effect on survival, improving median survival by approximately 6 weeks, according to a meta-analysis, and yielding a 1-year survival rate of approximately 20% (as compared with a rate of approximately 10% for supportive care).

TABLE 4Active newer agents for NSCLC chemotherapy

TABLE 5Results of selected randomized trials evaluating chemotherapy regimens of newer agents in advanced NSCLC

However, several chemotherapeutic agents have produced response rates in excess of 20% in NSCLC (Table 4). The potentially useful newer agents include the taxanes (paclitaxel and docetaxel), vinorelbine, gemcitabine, and irinotecan. Several of these drugs have unique mechanisms of action. Paclitaxel and docetaxel increase the polymerization of tubulin, gemcitabine is an antimetabolite, and irinotecan is a topoisomerase I inhibitor.

Furthermore, randomized trials demonstrated that a combination of a newer agent plus cisplatin significantly improves the response rate over cisplatin monotherapy (historically considered the most active agent against NSCLC). This increase in response rate translates into a significant, although modest, improvement in survival.

Optimal chemotherapy for advanced NSCLC

Until the early 1990s, regimens of cisplatin plus a vinca alkaloid or etoposide were most common. More recently, regimens that employ newer agents are more widely used. However, choosing one regimen from many options is a difficult task because there is no survival advantage documented for one regimen over another or for the standard regimen vs regimens containing newer agents.

Table 5 summarizes the results of select randomized trials in which combination regimens containing a newer agent are compared with old "standard" regimens or regimens containing another newer agent. Subtle differences in the eligibility criteria (eg, inclusion of patients with stage III tumors or those with poor performance status) make it difficult to directly compare the trial results. Nevertheless, there is a trend indicating that regimens containing newer agents show higher response rates and also better survival outcomes in some series than do older regimens.

Vinorelbine plus cisplatin combination. Vinorelbine was the first agent that demonstrated improved activity against NSCLC in combination with cisplatin. A European multicenter trial (Le Chevalier et al: J Clin Oncol 1994) showed the results favoring a cisplatin plus vinorelbine combination (vinorelbine, 30 mg/m² weekly; cisplatin, 120 mg/m² on days 1 and 29, then every 6 weeks) over a vindesine plus cisplatin combination (vindesine, 3 mg/m² weekly; cisplatin, 120 mg/m² on days 1 and 29, then every 6 weeks) and vinorelbine alone (30 mg/m² weekly). The median survival duration of 40 weeks in the vinorelbine/cisplatin treatment arm was significantly longer than the 32 weeks seen in the vindesine/cisplatin arm (P = .04) and 31 weeks in the vinorelbine monotherapy arm (P < .001). This trial, however, did not confirm the role of vinorelbine in NSCLC therapy, even though it confirmed the role of cisplatin.

To address this issue, SWOG conducted a study comparing cisplatin alone (100 mg/m² every 4 weeks) with the vinorelbine/cisplatin combination (cisplatin, 100 mg/m² every 4 weeks; vinorelbine, 25 mg/m² weekly × 3 every 4 weeks). Survival outcome was analyzed for 415 patients, 92% with stage IV tumors. The vinorelbine/cisplatin treatment significantly improved the disease progression–free survival (median, 2 months vs 4 months; P = .0001) and overall survival (median, 6 months vs 8 months; 1-year survival 20% vs 36%; P = .0018).

Paclitaxel plus platinum compound. A number of studies demonstrate promising results with paclitaxel in combination with cisplatin or carboplatin and other agents. Two large randomized trials compared paclitaxel plus cisplatin with standard regimens. In a three-arm, randomized trial (ECOG 5592) (Bonomi et al: J Clin Oncol 2000), 600 eligible patients with chemotherapy-naive stages IIIB-IV NSCLC were randomly assigned to receive a combination of cisplatin (75 mg/m²) plus etoposide (100 mg/m² daily on days 1 to 3) or either low-dose (135 mg/m² over 24 hours) or high-dose (250 mg/m² over 24 hours with growth factor) paclitaxel plus cisplatin (75 mg/m²). The response rates for the low-dose and high-dose paclitaxel arms were 26.5% and 32.1%, respectively, significantly better than for the cisplatin/etoposide arm (12%). Superior survival was observed with the combined paclitaxel regimens (median survival time, 9.99 months; 1-year survival rate, 39%) compared with etoposide plus cisplatin (median survival, 8 months; 1-year survival rate, 32%; P = .048). Comparing survival rates for the two dose levels of paclitaxel revealed no significant differences.

A European trial of similar design (Giaccone et al: J Clin Oncol 1998) reported that cisplatin/paclitaxel improved the response rate and quality-of-life parameters. There was no improvement in overall survival, however, compared with a standard regimen of cisplatin/teniposide (Vumon).

Paclitaxel/carboplatin has been the most widely favored regimen for first-line chemotherapy in all NSCLC stages among US medical oncologists, mainly because of promising phase II trial results and the ease of administration for outpatients, with manageable toxicity profiles compared with those of cisplatin-containing regimens. One of the early phase II trials, for example, reported a response rate of 62%, a median survival duration of 53 weeks, and a 1-year survival rate of 54%. However, a randomized trial sponsored by the manufacturer of paclitaxel failed to demonstrate a survival advantage over the standard cisplatin plus etoposide regimen. Nevertheless, paclitaxel plus carboplatin may remain a community standard because a SWOG trial reported results equivalent to the time-tested vinorelbine/cisplatin regimen (see Table 5).

Combination vs single-agent chemotherapy. A randomized phase III study conducted by CALGB further supported the superiority of combination chemotherapy over single-agent therapy. Previous trials had indicated that a platinum plus a novel agent was superior to a platinum alone. Lilenbaum et al demonstrated that for patients with stage IIIB or IV NSCLC, carboplatin and paclitaxel are superior to paclitaxel alone, even for patients with an ECOG performance status of 2. This randomized trial showed a median survival advantage for the combination therapy.

Gemcitabine plus cisplatin. Gemcitabine has also been approved by the FDA for use against NSCLC based on a series of successful phase II trials of cisplatin/gemcitabine and three major phase III trials. The HOG study, reported by Sandler et al, compared gemcitabine/cisplatin with cisplatin alone and showed a modest improvement in median and 1-year survival comparable to those seen in the vinorelbine trials. The Spanish and Italian trials, reported by Cardenal et al and Crinò et al, compared gemcitabine plus cisplatin with standard-regimen cisplatin plus etoposide and mitomycin plus ifosfamide plus cisplatin, respectively. Although there was a significant improvement in overall response, these two studies failed to demonstrate a survival benefit.

Because gemcitabine is relatively well tolerated without dose-limiting myelosuppression, it is being evaluated for use as a single agent or in combination with other agents in older or medically compromised patients. Italian investigators report that gemcitabine combined with the vinorelbine regimen is associated with significantly better survival than single-agent vinorelbine in elderly patients with NSCLC.

Other combination regimens that contain cisplatin plus newer agents, such as docetaxel or irinotecan, also showed similar results when compared with other two-drug regimens of either two newer or two older agents.

Major randomized trials comparing cytotoxic regimens

To identify a better chemotherapy regimen for advanced-stage NSCLC, the US cooperative study groups conducted large phase III trials. The SWOG investigators compared paclitaxel/carboplatin with vinorelbine/cisplatin (the time-tested regimen in previous European and SWOG trials). A total of 404 evaluable patients were randomized to receive either paclitaxel (225 mg/m² over 3 hours) plus carboplatin (at an AUC of 6 mg/mL/min on day 1) every 21 days or vinorelbine (25 mg/m² weekly) plus cisplatin (100 mg/m² on day 1) every 28 days. Overall response rates were 27% for both groups. The median survival times were also identical (8 months), with virtually identical 1-year survival rates (35% and 33%, respectively). Although both regimens provided effective palliation for advanced NSCLC, the investigators identified paclitaxel/carboplatin for future studies because of a favorable toxicity profile and better tolerability and compliance.

The ECOG 1594 trial compared three platinum-based regimens containing new agents in the treatment of NSCLC with a control arm of cisplatin and paclitaxel. The regimens were gemcitabine (1,000 mg/m² on days 1, 8, and 15) plus cisplatin (100 mg/m² on day 1) every 4 weeks, docetaxel (75 mg/m²) plus cisplatin (75 mg/m² on day 1) every 3 weeks, and paclitaxel (225 mg/m² over 3 hours) plus carboplatin (at an AUC of 6 mg/mL/min on day 1) every 21 days; the reference regimen was paclitaxel (175 mg/m² over 24 hours) plus cisplatin (75 mg/m² on day 1) every 21 days.

Analysis of 1,163 eligible patients showed no statistically significant differences in overall response, median survival, and 1-year survival rates when compared with the control arm, paclitaxel and cisplatin. Gemcitabine plus cisplatin was associated with a statistically significant prolongation of time to disease progression when compared with the control arm (4.5 months vs 3.5 months; P = .002) but was also associated with a higher percentage of grade 4 thrombocytopenia, anemia, and renal toxicity.

Randomized trials suggest that differentiating treatment regimens by histology may be important. A phase III trial by Scagliotti et al randomized 1,725 patients to receive a combination of cisplatin and gemcitabine vs cisplatin and pemetrexed. In patients who did not have a squamous cell histology, the combination of cisplatin and pemetrexed had a superior overall survival. On the other hand, in patients with a squamous cell histology, the combination of cisplatin and gemcitabine had a superior survival. These and other data suggest that pemetrexed and platinum appear to be superior in non–squamous cell populations. Overall survival was statistically superior for cisplatin/pemetrexed than for cisplatin/gemcitabine in patients with adenocarcinoma vs squamous histology (12.6 months vs 10.9 months; P = .03). In addition, cisplatin/pemetrexed provided efficacy similar to that of cisplatin/gemcitabine, with better tolerability, a reduced need for supportive therapies, and more convenient administration than cisplatin. This was the first phase III study in NSCLC to prospectively demonstrate a survival difference between platinum doublets based on histology. On the basis of the results of this study, the FDA approved pemetrexed, in combination with cisplatin, as the first-line treatment of locally advanced and metastatic NSCLC, for patients with a non-squamous histology.

Because all the regimens showed similar efficacy, quality of life becomes a critical issue in choosing a particular regimen. The decision to use one regimen over another will depend not only on ease of administration and side effects but also on the personal preference and experience of the treating oncologist.

Second-line chemotherapy for NSCLC

Before the new generation of more effective agents became available, few, if any, significant benefits were expected from second-line chemotherapy. As a result, reports in the literature seldom address this issue specifically or systematically. The most experience with second-line chemotherapy in NSCLC is with docetaxel, which has received FDA approval for this indication based on two randomized phase III trials confirming the promising phase II results of docetaxel monotherapy in patients with advanced NSCLC previously treated with platinum-based chemotherapy.

In a multicenter US trial (Fossella et al: J Clin Oncol 2000), 373 patients were randomized to receive either docetaxel (100 mg/m² [D100] or 75 mg/m² [D75]) or a control regimen of vinorelbine (30 mg/m²/wk) or ifosfamide (2 g/m² × 3 days) every 3 weeks. Overall response rates were 10.8% with D100 and 6.7% with D75, each significantly higher than the 0.8% response of the control arm (P = .001 and P = .036, respectively). Although overall survival was not significantly different among the three groups, the 1-year survival was significantly higher with D75 than with the control treatment (32% vs 19%; P = .025).

In a phase III trial led by Hanna et al, 572 previously treated patients were randomized to receive pemetrexed with vitamin B₁₂, folic acid, and dexamethasone or docetaxel with dexamethasone. The overall response rate in the pemetrexed arm was higher, 9.1% vs 8.8%. The median disease progression–free survival was 2.9 months for each arm, and the median survival favored pemetrexed (8.3 months vs 7.9 months). The 1-year survival for each arm was 29.7%. Adverse reactions (grade 3/4) were more severe with docetaxel.

The second trial (Shepherd et al: J Clin Oncol 2000) compared single-agent docetaxel with best supportive care. The initial docetaxel dose was 100 mg/m², which was changed to 75 mg/m² midway through the trial because of toxicity. A total of 204 patients were enrolled; 49 received D100, 55 received D75, and 100 received best supportive care. Treatment with docetaxel was associated with significant prolongation of survival (7 months vs 4.6 months; log-rank test, P = .047) and time to disease progression (10.6 weeks vs 6.7 weeks; P < .001).

Hanna et al conducted a noninferiority trial to test whether pemetrexed was equivalent to docetaxel in the second-line setting. They randomized 571 patients to receive 500 mg/m² of pemetrexed or 75 mg/m² of docetaxel preceded by a vitamin B₁₂ injection every two cycles. The median survival on the two arms was equivalent, but the pemetrexed arm had significantly less grade 3/4 neutropenia and fewer hospitalizations overall. On the basis of this study, the FDA approved pemetrexed for second-line therapy for NSCLC.

Duration of chemotherapy

ASCO has recently updated recommendations on chemotherapy for stage IV NSCLC. Two-drug cytotoxic combinations should be administered for no more than six cycles. For those with stable disease or response after four cycles, immediate treatment with an alternative, single-agent chemotherapy such as pemetrexed in patients with non-squamous histology, docetaxel in unselected patients, or erlotinib in unselected patients may be considered. Limitations of this data are such that a break from cytotoxic chemotherapy after a fixed course is also acceptable, with initiation of second-line chemotherapy at disease progression.

Evidence for maintenance therapy

Several trials have suggested that there may be some benefit to maintenance chemotherapy or targeted biologic agents in patients who have response or stable disease after front-line therapy.

Switch maintenance. Fidias et al suggested that adding docetaxel as maintenance therapy after platinum-based front-line chemotherapy can delay tumor progression and lead to improvements in disease-free survival.

Ciuleanu et al demonstrated an improvement in progression-free survival (4.3 months vs 2.6 months; P < .001) and overall survival (13.4 months vs 10.6 months; P = .012) for switch maintenance chemotherapy with pemetrexed after four cycles of a non–pemetrexed-containing platinum doublet.

SATURN (Sequential Tarceva in Unresectable NSCLC) was an international phase III study of 889 patients that compared maintenance erlotinib (Tarceva) with placebo in patients who had received four cycles of front-line therapy. Cappuzzo et al demonstrated that maintenance erlotinib given immediately after first-line chemotherapy significantly increased progression-free survival in both wild-type and EGFR mutation–positive patients, with HRs of 0.78 and 0.10, respectively. Maintenance erlotinib is a reasonable option for patients without an EGFR mutation, but the benefit is not quite as dramatic as results seen for patients with the mutation.

The BETA (Bevacizumab/Tarceva) trial had previously compared bevacizumab in combination with erlotinib vs erlotinib alone for the treatment of advanced NSCLC after failure of first-line chemotherapy. This phase III trial demonstrated improved progression-free survival in the combination arm. Thus, ATLAS (A Study Comparing Bevacizumab Therapy With or Without Erlotinib for First-Line Treatment of Non-Small Cell Lung Cancer) was designed to compare maintenance therapy using bevacizumab and erlotinib with bevacizumab alone following first-line therapy using bevacizumab and a platinum-containing doublet in patients with stage IIIB/IV NSCLC. The data safety monitoring committee stopped the trial early, because it met the primary endpoint, showing that the median progression-free survival was 4.8 months for the combination arm and 3.7 months for the bevacizumab-only arm. Bevacizumab has known side effects, including impaired wound healing, proteinuria, and hypertension. Survival data will be available in the next few years.

Continuation maintenance. Paz-Ares et al recently published the PARAMOUNT study, which demonstrated an improvement in progression-free survival and overall survival for patients with advanced non-squamous NSCLC who responded to four cycles of induction cisplatin/pemetrexed chemotherapy and who continued on maintenance pemetrexed until disease progression. The median progression-free survival, measured from randomization, was 4.1 months (95% CI, 3.2–4.6) for pemetrexed and 2.8 months (95% CI, 2.6–3.1) for placebo. Median overall survival was increased from 14 months for placebo to 16.9 months for patients who received maintenance pemetrexed.

Promising agents and personalized therapies

Several novel agents are being developed for the treatment of solid tumors, including lung cancer. These include signal transduction inhibitors, such as tyrosine kinase inhibitors (eg, erlotinib, gefitinib); small-molecule tyrosine kinase inhibitors of VEGF, such as sunitinib (Sutent) and sorafenib (Nexavar); and antiangiogenic agents, including monoclonal antibodies, such as bevacizumab, cetuximab, and trastuzumab (Herceptin). Many of these novel agents are being tested in combination with chemotherapeutic agents, because their mechanisms of action suggest that they may be far more effective as long-term inhibitors of cancer progression than as classic cytotoxics.

Combinations of cetuximab with chemotherapy also appear promising. Pirker et al showed that adding cetuximab to cytotoxic chemotherapy with cisplatin and vinorelbine improved median survival from 10.1 months to 11.3 months in a randomized trial of 1,125 patients with advanced and metastatic NSCLC. This statistically significant (P = .044) 1.2-month improvement in median survival was not duplicated when cetuximab was added to taxane/platinum-based chemotherapy. However, in both of these studies, adding cetuximab to chemotherapy improved response rate, and these data are being evaluated in their totality as physicians integrate this EGFR antibody into the therapeutic paradigm for NSCLC.

Gefitinib and erlotinib. To date, most phase I studies of previously mentioned biologic compounds have suffered from a difficulty in developing pharmacologically or molecularly driven endpoints that will serve as reasonable intermediate biomarkers of efficacy or even surrogates for toxicity. Further research has focused on the novel small-molecule tyrosine kinase inhibitors erlotinib and gefitinib. Two phase II trials of gefitinib in the second- and third-line settings were conducted in Europe and Japan. Patients were randomized to receive gefitinib at either 250 or 500 mg daily. The drug was found to be active, with an 11% to 18% response rate, and there was no superiority for the higher dose. Similar data were seen for erlotinib.

Unfortunately, randomized combination trials of gefitinib at 250 and 500 mg daily with cytotoxic chemotherapy, either paclitaxel and carboplatin in one trial or gemcitabine and cisplatin in the other study vs placebo in front-line therapy, failed to demonstrate any survival advantage. These results have cast a pall over the development of tyrosine kinase inhibitors in combination with chemotherapy. Regardless, the question of whether or not to approve these new agents for third-line therapy of lung cancer in cisplatin/docetaxel-refractory patients remains open for debate.

The activity demonstrated by gefitinib and erlotinib as single agents in advanced NSCLC generated much optimism, including a recent trial indicating that erlotinib improved survival (by a median of 2 months) in the second- and third-line treatments of NSCLC, with a substantial increase in 1-year survival (P < .001). After the initial successes with chemotherapy and promising results from targeted tyrosine kinase inhibitors in stages IIIB and IV NSCLC, several large phase III trials of either gefitinib or erlotinib in combination with conventional platinum-based chemotherapy were conducted as the INTACT (Iressa NSCLC Trial Assessing Combination Treatment) 1 and INTACT 2 trials or the TALENT (Tarceva Lung Cancer Investigation) and TRIBUTE (Tarceva Responses in Conjunction with Paclitaxel and Carboplatin) trials.

The phase III trials of single-agent erlotinib and gefitinib, when compared with best supportive care in the second- and third-line settings, had dramatically different results. Shepherd et al conducted a randomized trial of erlotinib (150 mg daily) vs placebo in 723 patients previously treated with front- or second-line chemotherapy for NSCLC. A total of 488 patients received erlotinib and 243 received placebo.

The median overall survival significantly favored the erlotinib arm (6.7 months vs 4.7 months), with a reduction in the HR of 0.73 (P > .001), as did the 1-year survival rate (31% vs 21%; P > .01). Quality of life and median time to deterioration also significantly favored erlotinib. On the other hand, the phase III trial of gefitinib vs best supportive care in more than 1,600 patients was reported and showed no significant advantage to gefitinib at 250 mg daily in a patient population with a significant number of active smokers.

For patients who have the classic exon 19 or 21 mutation, erlotinib and gefitinib provide a significant advantage over standard chemotherapy. However, some patients are resistant or develop a T790M mutation; this mutation adds a bulky methionine group in the adenosine triphosphate binding pocket, which sterically hinders the attachment of tyrosine kinase inhibitors.

IPASS (Iressa Pan-Asia Study) was a phase III, multicenter, randomized, open-label, parallel-group study of 1,217 select never- or light-smoking patients in East Asia who had advanced NSCLC and received either gefitinib or carboplatin plus paclitaxel as first-line treatment. The primary endpoint was progression-free survival; the secondary endpoints included overall survival, for which the analysis is ongoing. The 12-month rates of progression-free survival were 24.9% with gefitinib and 6.7% with carboplatin-paclitaxel (P < .001). On the basis of these data and those of SATURN, the FDA approved erlotinib for first-line maintenance treatment of locally advanced or metastatic NSCLC in patients whose disease has not progressed after four cycles of platinum-based chemotherapy. Subsequent data analysis has led to the approval of erlotinib as first-line therapy for stage IV NSCLC with sensitizing mutations of EGFR.

Two trials reported in 2011 provided evidence of the superiority of erlotinib in EGFR mutation–positive patients, one in a Chinese population (OPTIMAL) and a second in a European population (EURTAC). OPTIMAL demonstrated that erlotinib improved progression-free survival and quality of life compared with gemcitabine/carboplatin (13.7 months vs 4.6 months). Similarly, EURTAC showed progression-free survival of 9.4 months in the erlotinib arm vs 5.2 months in the platinum-based chemotherapy arm. EURTAC also investigated overall survival, which was not significantly different; this finding is possibly explained by the fact that crossover was allowed on progression.

Bevacizumab. When combined with chemotherapy, bevacizumab appears to result in a significant survival advantage for patients with advanced NSCLC. On the basis of promising phase II data of bevacizumab in combination with carboplatin and paclitaxel, Sandler et al randomized 878 patients to receive either bevacizumab with carboplatin and paclitaxel or carboplatin and paclitaxel alone.

There was a significant increase in the response rate for the combination (27.2%) with bevacizumab vs paclitaxel and carboplatin alone (10%; P < .001), and both median and progression-free survival significantly favored the bevacizumab combination arm (overall survival: 12.5 months vs 10.2 months; P = .007; HR = 0.77; 95% CI, 0.65–0.93; progression-free survival: 6.4 months vs 4.5 months; P < .001; HR = 0.62; 95% CI, 0.53–0.72). As in the phase II trial, this study reported a total of eight treatment-related deaths in the bevacizumab arm vs two in the paclitaxel and carboplatin arm. A second phase III randomized trial testing the value of adding bevacizumab to gemcitabine and cisplatin therapy showed an improvement in disease-free survival, but not overall survival.

Other promising novel agents now under investigation in lung cancer include inhibitors of the insulin-like growth factor (IGF) receptor. Karp et al showed that these agents appear to be particularly promising in patients with squamous cell lung tumors, with response rates in a small study as high as 70%. As more pathways involved in NSCLC are found, more clinical trials involving inhibitors of phosphoinositide 3-kinase, IGF, and c-MET (where sensitivity is predicted by a mutation in BRAF [B-Raf proto-oncogene serine/threonine-protein kinase]) are being initiated. MET expression is associated with poor outcome in NSCLC. A recent study compared erlotinib plus a monoclonal antibody the binds to the Met receptor (MetMAb) with erlotinib plus placebo in patients with increased expression of c-MET measured by immunohistochemistry. Patients in the MetMAb arm had progression-free survival of 3 months vs 1.5 months for patients in the placebo arm. Overall survival was 12.6 months vs 4.6 months for the placebo arm.

Personalized therapies

Evaluation of NSCLC involves distinction between a squamous lesion or adenocarcinoma and of actual genetic differences. Pemetrexed and bevacizumab are used in non-squamous histology, and erlotinib is given for EGFR mutations, but other oncogene addictions are becoming apparent. ALK gene rearrangement occurs in 4% of NSCLC patients with EML4 (echinoderm microtubule-associated protein-like 4) as its most common fusion partner. EML4-ALK is seen in up to 20% of nonsmokers and in about 30% of patients who are never-smokers and EGFR wild-type. It is strongly associated with signet ring cell histology. Crizotinib (Xalkori), an ALK inhibitor, has been found to improve overall survival in EML4-ALK mutation–positive patients in both first-line and second-line treatment. In first-line therapy, 2-year overall survival was 64% vs 33% for historical controls. In second- and third-line therapy, 2-year overall survival was 61% vs 9% for historical controls. Early results from a second, ongoing study in patients who had progressed after at least one chemotherapy regimen reported 83% of patients had tumor shrinkage and most patients had clinically significant improvements in pain, cough, dyspnea, and fatigue. Recent data suggest that crizotinib also has activity in NSCLC harboring a ROS1 gene rearrangement.

Phase 2 data presented at the 2012 ASCO Annual Meeting suggest that patients with tumors harboring mutations in KRAS, a poor prognostic mutation that predicts resistance to EGFR agents and standard cytotoxic chemotherapy, may derive benefit from treatment with the mTOR inhibitor ridaforolimus.

Very encouraging data with the anti-programmed death-1 (anti-PD-1) antibody, BMS-936558, have also been reported. PD-1 is an immune checkpoint molecule involved in suppression of T-cell–mediated anti-tumor immunity. In 76 patients with advanced refractory NSCLC treated with single-agent anti-PD-1 in a recent phase I study, the objective response rate was 18%, with more than a quarter of patients progression-free at 6 months. Strategies being investigated prospectively to maximize the effectiveness of PD-1 inhibition may include sequencing with chemotherapy, co-inhibition with other immune checkpoint inhibitors, and combination with other targeted agents.

TABLE 6Single-agent chemotherapy regimens for NSCLC

TABLE 7Combination chemotherapy regimens recommended for NSCLC

Current treatment recommendations

It is important to note that patients who have lost significant amounts of weight or who have a poor performance status are at greater risk for toxicity, including a higher likelihood of lethal toxicity, when they are treated with modest doses of chemotherapy. On the basis of currently available data, a reasonable approach for patients with stage IV NSCLC who have a good performance status (ECOG performance status 0/1) and have not lost a significant amount of weight (< 5% of usual weight) would be to encourage them to participate in a clinical trial. However, it would also be appropriate to treat this group of patients with etoposide plus cisplatin or with one of the newer combination regimens, such as gemcitabine/cisplatin, vinorelbine/cisplatin, paclitaxel/cisplatin, paclitaxel/carboplatin, or docetaxel/cisplatin (Tables 6 and 7).

Role of Photodynamic Therapy

Photodynamic therapy (PDT), which combines porfimer sodium (Photofrin), a hematoporphyrin derivative in which the less active porphyrin monomers have been removed with an argon-pumped dye laser, has been explored in a variety of different tumors, with varying results. Several investigators have reported excellent results with PDT in early-stage head and neck cancers as well as intrathoracic tumors. However, initial studies have involved a limited number of patients.

Although this novel technique seems to be extremely promising, it appears to be applicable to only a minority of patients with NSCLC. Nevertheless, PDT appears to be particularly useful for the treatment of early-stage lung cancer for a variety of reasons. First, it appears to preserve lung function and can be repeated as additional tumors appear—an important consideration, because such patients appear to be at high risk for developing other new tumors. Second, this technique does not preclude ultimate surgical intervention when deemed necessary.

Results in early-stage NSCLC

In a prospective phase II study (Furuse et al: J Clin Oncol 1993), 54 patients with 64 early-stage lung cancers received Photofrin (2 mg/kg) and 630-nm illumination of 100 to 200 J/cm². Of 59 assessable tumors, 50 responded completely and 6 showed partial responses. Five patients with complete response developed recurrences 6 to 18 months after treatment.

The major predictor of response in this study was tumor length. The likelihood of achieving a complete response was 97.8% if the tumor was smaller than 1 cm, as opposed to only 42.9% if the lesion was larger than 1 cm. The overall survival rate in these patients was 50% at 3 years.

A similar study by Kato et al also indicated a 96.8% complete response rate for tumors smaller than 0.5 cm but only a 37.5% rate for tumors larger than 2 cm. The overall 5-year survival rate for the 75 patients treated in this study was 68.4%, which is acceptable by current standards.

Results in advanced-stage NSCLC

Two prospective randomized trials (European and US/Canadian) compared PDT with the neodymium:yttrium-aluminum-garnet (Nd:YAG) laser for treatment of partially obstructive, advanced NSCLC. Investigators analyzed results from the two trials both individually and collectively. Collective analysis included data from 15 centers in Europe and 20 centers in the United States and Canada, and it involved a total of 211 patients. In the European trial, 40% of the patients had received previous therapy, whereas in the US/Canadian trial, all of the patients had received previous treatment.

Tumor response was similar for both therapies at 1 week. At 1 month, however, 61% and 42% of the patients treated with PDT in the European and US/Canadian trials, respectively, were still responding, compared with 36% and 19% of patients who underwent laser therapy in the two trials.

PDT also produced more dramatic improvements in dyspnea and cough than did Nd:YAG therapy in the European trial, but the two treatments had similar effects on these symptoms in the US/Canadian trial. Both sets of investigators concluded that PDT appears to be superior to laser therapy for the relief of dyspnea, cough, and hemoptysis. Also, the overall incidence of adverse reactions was similar with the two therapies (73% for PDT vs 64% for Nd:YAG therapy).

Palliation of Local and Distant Symptoms

Radiation therapy

Many patients with lung cancer experience distressing local symptoms at some time. They may arise from airway obstruction by the primary tumor, compression of mediastinal structures by nodal metastases, or metastatic involvement of distant organs. Radiation therapy is effective in palliating most local symptoms as well as symptoms at common metastatic sites, such as bone and brain. For select patients with a solitary brain metastasis and controlled disease in other sites, resection followed by irradiation appears to be superior to radiation therapy alone in improving both survival and quality of life. (For more information regarding management of brain metastases, see "Primary and Metastatic Brain Tumors" chapter.)

TABLE 8Percentage of patients with symptoms of NSCLC palliated by external-beam irradiation

Recently, an American Society for Radiation Oncology (ASTRO) committee cochaired by Rodrigues and Movsas developed an evidence-based guideline for palliative radiotherapy in cancer. Overall, higher-dose/fractionation palliative external beam radiation therapy (EBRT) regimens (eg, 30 Gy/10 fraction equivalent or greater) are associated with modest improvements in survival and total symptom score, particularly in patients with good performance status. Because these improvements are associated with an increase in esophageal toxicity, however, various shorter EBRT dose/fractionation schedules (eg, 20 Gy in five fractions, 17 Gy in two weekly fractions, 10 Gy in one fraction), which provide good symptomatic relief with fewer side effects, can be used for patients who request a shorter treatment course and/or in those with a poor performance status. Integration of concurrent chemotherapy with palliative intent/fractionated radiotherapy is not currently supported by the medical literature. In general, in the United States, radiation oncologists often use doses of approximately 30 Gy in 10 fractions for palliative thoracic treatment in lung cancer. Data from the United Kingdom suggest that similar efficacy without greater toxicity may be achieved with more abbreviated schedules, such as 17 Gy in two fractions 1 week apart or single fractions of 10 Gy (see Table 8). Such schedules may facilitate the coordination of irradiation and chemotherapy and reduce patient travel and hospitalization.

Endobronchial irradiation. Cobalt-60 or iridium-192 has been used to palliate symptoms arising from partial airway obstruction, including cough, dyspnea, and hemoptysis. The dosimetric advantage of being able to deliver a high radiation dose to the obstructing endobronchial tumor while sparing adjacent normal structures, such as the lungs, spinal cord, and esophagus, has clear appeal, particularly in the patient whose disease has recurred following prior EBRT. Although good rates of palliation have been reported with endobronchial irradiation, significant complications, including fatal hemoptysis, are seen in 5% to 10% of patients. It remains unclear, however, how often this complication is actually due to the irradiation or the underlying disease itself.

Endobronchial brachytherapy (EBB) should be considered as one of several approaches (including laser excision, cryotherapy, and stent placement) used in the management of patients with symptomatic airway obstruction, and management should be individualized. All of these approaches are more suitable for partial than for complete airway obstruction. Overall, EBB can be a reasonable option for the palliation of endobronchial lesions that cause obstructive symptomatology, including lung collapse, or for hemoptysis, after EBRT failure.

Chemotherapy

Several trials have explored the use of chemotherapy to palliate specific symptoms in patients with lung cancer. In general, these trials have found that rates of symptomatic improvement were considerably higher than objective response rates and were not dissimilar to symptomatic response rates with local radiation therapy.

Thus, although radiation therapy remains the most appropriate modality for treatment of problems such as superior vena cava obstruction, spinal cord compression, brain metastases, or localized bone pain, patients who have more extensive disease without these local emergencies may be considered for palliative chemotherapy, which may relieve local symptoms and prolong survival.

Bisphosphonates

Approximately 30% to 65% of patients with advanced lung cancer develop bone metastases. The median survival following development of bone metastases is 6 months. Bone disease is associated with significant morbidity, including severe pain, hypercalcemia of malignancy, pathologic fracture, and spinal cord or nerve root compression. Treatment of bone metastases may include surgical intervention, radiation therapy, and chemotherapy. Bisphosphonate treatment can decrease skeleton-related complications, delay progressive disease, and relieve bone pain.

Bisphosphonates such as clodronate, pamidronate, and zoledronic acid (Zometa) exhibit strong affinity for the hydroxyapatite crystal of bone and preferentially accumulate at sites of active bone remodeling, where they prevent bone resorption. They provide effective treatment for hypercalcemia of malignancy and have been shown to delay the onset of progressive bone disease and relieve bone pain in studies largely performed in patients with metastases secondary to breast cancer, multiple myeloma, and prostate cancer. Nitrogen-containing bisphosphonates, such as pamidronate and zoledronic acid, appear to exert antitumor effects. Zoledronic acid has also been found to have pronounced antinociceptive effects, which have been absent with other bisphosphonates in preclinical studies. Zoledronic acid is the only bisphosphonate shown to be effective in reducing skeletal complications in patients with bone metastases from lung cancer and solid tumors other than breast and prostate cancers.

Follow-Up of Long-Term Survivors

At present, no standard follow-up protocol exists for patients with cured NSCLC or SCLC. However, long-term follow-up should at least include serial physical examinations once the patient has reached the 5-year mark. There is some controversy about the value of using CT scanning or even chest radiography for the long-term follow-up of these patients.

In this vein, retrospective reviews of the literature have revealed that patients with SCLC appear to have the highest rate of second primary tumor development—as high as 30%—over the course of their lifetime, with some studies reporting annual second primary tumor rates of 5% to 10%. Therefore, the concept of chemoprevention appears to have particular merit in these patients.

A randomized chemoprevention study of patients with stage I NSCLC showed a surprisingly high annual recurrence rate of 6.5% in patients with T1 tumors, as opposed to 11.2% in patients with T2 tumors. There is clearly a need for effective chemoprevention for both of these tumor subsets, as well as the establishment of consistent guidelines for routine long-term follow-up.