Resected/Resectable Stage IIIA N2 Disease
        Unresectable Stage IIIA N2 NSCLC
Current Clinical Trials

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Stage IIIA non-small cell lung cancer (NSCLC) is defined by the following clinical stage groupings:

• T1, N2, M0
• T2, N2, M0
• T3, N1, M0
• T3, N2, M0

Patients with stage IIIA NSCLC are a heterogenous group. Patients may have metastases to ipsilateral mediastinal nodes or potentially resectable T3 tumors invading chest wall or mediastinal involvement with metastases to peribronchial or hilar lymph nodes (N1). Presentations of disease range from resectable tumors with microscopic metastases to lymph nodes to unresectable, bulky disease involving multiple nodal stations.

Patients with clinical stage IIIA-N2 disease have a 5-year survival rate of 10% to 15% overall; however, patients with bulky mediastinal involvement (i.e., visible on chest radiography) have a 5-year survival rate of 2% to 5%. Depending on clinical circumstances, the principal forms of treatment that are considered for patients with stage IIIA NSCLC are radiation therapy, chemotherapy, surgery, and combinations of these modalities.

Despite careful preoperative staging, some patients will be found to have metastases to mediastinal N2 lymph nodes at thoracotomy. Preoperative staging typically includes the following:

• Computed tomography (CT) scan.
• Positron emission tomography (PET).
• Mediastinoscopy.

If complete resection of tumor and lymph nodes is possible, such patients may benefit from surgery followed by postoperative adjuvant chemotherapy. The Cochrane Collaboration group reviewed 11 randomized trials with a total of 1,910 patients who underwent surgical interventions for early stage (I–IIIA) lung cancer.[1] From a pooled analysis of three trials, 4-year survival was superior in patients with resectable stage I to IIIA NSCLC who underwent resection and complete ipsilateral mediastinal lymph node dissection (CMLND) compared with those who underwent resection and lymph node sampling; the hazard ratio (HR) was estimated to be 0.78 (95% confidence interval [CI], 0.65–0.93, P = .005).[1][Level of evidence: 1iiA]

Conclusions about the efficacy of surgery for patients with local and locoregional NSCLC are limited by the small number of participants studied to date and by the potential methodological weaknesses of the trials. Current evidence suggests that lung cancer resection combined with CMLND is associated with a small-to-modest improvement in survival compared with lung cancer resection combined with systematic sampling of mediastinal nodes in patients with stage I to IIIA NSCLC.[1][Level of evidence: 1iiA] CMLND versus lymph node sampling has been evaluated in a large randomized phase III trial (ACOSOG-Z0030). Preliminary analyses of operative morbidity and mortality showed comparable rates from the procedures.[2]

Evidence from randomized controlled clinical trials indicates that chemotherapy after complete resection of stage IIIA NSCLC encountered unexpectedly at surgery improves survival. Several randomized controlled trials and meta-analyses have evaluated the use of adjuvant chemotherapy in patients with stage I, II, and IIIA NSCLC.[3-9]

In the largest meta-analysis based on individual patient outcomes, data were collected and pooled from the five largest trials (4,584 patients) that were conducted after 1995 of cisplatin-based chemotherapy in patients with completely resected NSCLC.[5] With a median follow-up time of 5.2 years, the overall HR of death was 0.89 (95% CI, 0.82–0.96; P = .005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy. The effect of chemotherapy did not vary significantly (test for interaction, P = .11) with the associated drugs, including vinorelbine (HR = 0.80; 95% CI, 0.70–0.91), etoposide or vinca alkaloid (HR = 0.92; 95% CI, 0.80–1.07), or other (HR = 0.97; 95% CI, 0.84–1.13). The greater effect on survival observed with the doublet of cisplatin plus vinorelbine compared with other regimens should be interpreted with caution as the total dose of cisplatin received was significantly higher in patients treated with vinorelbine. The benefit varied with stage, however, the HR for stage IIIA was 0.83; 95% CI, 0.72–0.94.

Two trials (IALT and ANITA) reported significant overall survival (OS) benefits associated with adjuvant chemotherapy in stage IIIA disease.[4,10] For the subgroup of stage IIIA patients in ANITA (n = 325), the HR was 0.69 (95% CI, 0.53–0.90), and the result for the IALT trial (n = 728) was HR = 0.79 (95% CI, 0.66–0.95). Chemotherapy effect was higher in patients with better PS.

There was no interaction between the chemotherapy effect and any of the following:

• Sex.
• Age.
• Histology.
• Type of surgery.
• Planned radiation therapy.
• Planned total dose of cisplatin.

In a retrospective analysis of a phase III trial of adjuvant cisplatin and vinorelbine, patients greater than 65 years were found to benefit from treatment.[11] Chemotherapy significantly prolonged OS for elderly patients (HR = 0.61; 95% CI, 0.38 to 0.98; P = .04). There were no significant differences in toxic effects, hospitalization, or treatment-related death by age group although elder patients received less treatment. Based on these data, patients with completed resected stage IIIA NSCLC may benefit from adjuvant cisplatin-based chemotherapy.[5] [Level of evidence: 1iiA]

The role of chemotherapy prior to surgery in patients with stage III-N2 NSCLC has been extensively tested in clinical trials. The proposed benefits of preoperative chemotherapy are:

• A reduction in tumor size that may facilitate surgical resection.
• Early eradication of micrometastases.
• Better tolerability.

The Cochrane Collaboration group provided a systematic review and meta-analysis of seven randomized controlled trials that included 988 patients and an evaluation of the addition of preoperative chemotherapy to surgery versus surgery alone.[12] Included trials evaluated patients with stages I, II, and IIIa NSCLC. Preoperative chemotherapy provided an absolute benefit in survival of 6% across all stages of disease from 14% to 20% at 5 years (HR = 0.82; 95% CI, 0.69–0.97; P = .022).[12][Level of evidence: 1iiA] This analysis was unable to address questions such as whether particular types of patients may benefit more or less from preoperative chemotherapy.[10]

In the largest trial reported to date, 519 patients were randomized to receive either surgery alone, or three cycles of platinum-based chemotherapy followed by surgery.[13] Most patients (61%) had clinical stage I disease, 31% had stage II disease, and 7% had stage III disease. Postoperative complications were similar between groups, and no impairment of quality of life was observed. There was no evidence of a benefit in terms of OS (HR = 1.02; 95% CI, 0.80–1.31; P = .86). Updating the systematic review by addition of the present result suggests a 12% relative survival benefit with the addition of neoadjuvant chemotherapy (1,507 patients, HR = 0.88; 95% CI, 0.76–1.01; P = .07), equivalent to an absolute improvement in survival of 5% at 5 years.[13]

The value of postoperative radiation therapy (PORT) has been assessed.[14] Although some studies suggest that PORT can improve local control for node-positive patients whose tumors were resected, it remains controversial whether it can improve survival. A meta-analysis of 10 randomized trials that evaluated PORT versus surgery alone showed no difference in OS for the entire PORT group or for the subset of N2 patients.[4][Level of evidence: 1iiA]

Results from a nonrandomized subanalysis from one randomized trial of adjuvant chemotherapy [10] and from SEER suggest that there is benefit of PORT in stage IIIA-N2 disease, and the role of PORT should be clarified in ongoing phase III trials. The large (n = 7,465) SEER retrospective study found superior survival rates associated with radiation therapy in N2 disease (HR = 0.855; 95% CI, 0.762–0.959). In addition, a nonrandomized subanalysis of the ANITA trial, comparing 5-year OS in N2 patients who did or did not receive PORT, found higher survival rates in patients receiving radiation therapy in both the observation and chemotherapy arms (21% vs. 17% and 47% vs. 34%, respectively; [statistical tests of comparison were not conducted]).[15] The majority of studies cited used doses ranging from 30 Gy to 60 Gy, typically provided in 2 Gy to 2.5 Gy fractions.

The optimal dose of postoperative thoracic radiation therapy is not known at this time. Further analysis is needed to determine whether these outcomes can be modified with technical improvements, better definitions of target volumes, and limitation of cardiac volume in the radiation portals.[4]

As referred to in the National Cancer Institute of Canada and Intergroup Study JBR.10 study (CAN-NCIC-BR10 and JBR.10), PORT may be considered in selected patients to reduce the risk of local recurrence, if there is:[11]

• Involvement of multiple nodal stations.
• Extracapsular tumor spread.
• Close or microscopically positive resection margins.

Five randomized trials have assessed the value of adjuvant combination chemoradiation therapy versus radiation following surgical resection.[12-16][Level of evidence: 1iiA] Only one trial reported improved disease-free survival (DFS) and no trial reported improved OS. Combination chemotherapy and radiation administered before or following surgery should be viewed as investigational and requiring evaluation in future clinical trials.

Three trials have evaluated platinum-based combination chemotherapy followed by surgery versus combined platinum-combination chemoradiation therapy (60 Gy–69.6 Gy) alone to determine which local treatment modality (surgery or radiation therapy) was most efficacious.[16-18] Although studies were small, enrolling 73, 107, and 333 patients with stage IIIA-N2 disease, respectively, no trial reported a difference in local control or survival.[16-18][Level of evidence: 1iiA].

In the largest series (EORTC-08941), 579 patients with histologic- or cytologic-proven stage IIIA-N2 NSCLC were given three cycles of platinum-based induction chemotherapy.[18] The 333 responding patients were subsequently randomly assigned to surgical resection or radiation therapy. Of the 154 (92%) patients who underwent surgery, 50% had a radical resection, 42% had a pathologic downstaging, and 5% had a pathologic complete response; 4% died after surgery. PORT was administered to 62 (40%) patients in the surgery arm. Among the 154 (93%) patients who received radiation therapy, overall compliance to the radiation therapy prescription was 55%, and grade 3–4 acute and late esophageal and pulmonary toxic effects occurred in 4% and 7% of patients; one patient died of radiation pneumonitis. Median and 5-year OS for patients randomly assigned to resection versus radiation therapy were 16.4 versus 17.5 months and 15.7% versus 14%, respectively (HR = 1.06; 95% CI, 0.84–1.35). Rates of progression-free survival were also similar in both groups. In view of its low morbidity and mortality, it was concluded that radiation therapy should be considered the preferred locoregional treatment for these patients.

In summary, the preponderance of evidence indicates that adjuvant cisplatin combination chemotherapy provides a significant survival advantage to patients with resected NSCLC with occult N2 disease discovered at surgery. The optimal sequence of surgery and chemotherapy and the benefits and risks of adjuvant radiation therapy in patients with resectable NSCLC are yet to be determined.

Treatment options for patients with resected/resectable disease:

1. Surgery followed by postoperative adjuvant chemotherapy.
2. Clinical trials of combined modality therapy.

Radiation therapy alone, administered sequentially with chemotherapy and concurrently with chemotherapy, may provide benefit to patients with locally advanced unresectable stage III NSCLC. However, combination chemoradiation therapy delivered concurrently provides the greatest benefit in survival with increase in toxic effects. Radiation therapy with traditional dose and fractionation schedules (1.8–2.0 Gy per fraction per day to 60–70 Gy in 6 to 7 weeks) results in reproducible long-term survival benefit in 5% to 10% of patients and significant palliation of symptoms.[19] One prospective randomized clinical study showed that radiation therapy given continuously (including weekends) as three daily fractions (CHART) improved OS compared with radiation therapy given as one daily fraction.[20][Level of evidence: 1iiA] Patterns of failure for patients treated with radiation therapy alone included both locoregional and distant failures.

Although patients with unresectable stage IIIA disease may benefit from radiation therapy, long-term outcomes have generally been poor because of local and systemic relapse. The addition of sequential and concurrent chemotherapy to radiation therapy has been evaluated in prospective randomized trials. A meta-analysis of patient data from 11 randomized clinical trials showed that cisplatin-based combinations plus radiation therapy resulted in a 10% reduction in the risk of death compared with radiation therapy alone.[21][Level of evidence: 1iiA] Meta-analysis of the 13 trials (based on 2,214 evaluable patients) showed that the addition of concurrent chemotherapy to radical radiation therapy reduced the risk of death at 2 years (RR = 0.93; 95% CI, 0.88–0.98, P = .01). For the 11 trials with platinum-based chemotherapy, RR was 0.93 (95% CI, 0.87–0.99, P = .02).[22] In a meta-analysis of individual data from 1,764 patients, which was based on nine trials, the HR of death among patients treated with radiation chemotherapy compared to radiation therapy alone was 0.89 (95% CI, 0.81–0.98; P = .02) corresponding to an absolute benefit of chemotherapy of 4% at 2 years. The combination of platinum with etoposide seemed more effective than platinum alone. Concomitant platinum-based radiation chemotherapy may improve survival of patients with locally advanced NSCLC. However, the available data are insufficient to accurately define the size of such a potential treatment benefit and the optimal schedule of chemotherapy.[23]

The results of two randomized trials (including RTOG-9410) and a meta-analysis (NPC 95-01) indicate that concurrent chemotherapy and radiation therapy provide greater survival benefit albeit with more toxic effects than sequential chemotherapy and radiation therapy.[24-26][Level of evidence: 1iiA] In the first trial, the combination of mitomycin C, vindesine, and cisplatin were given concurrently with split-course daily radiation therapy to 56 Gy compared to chemotherapy followed by continuous daily radiation therapy to 56 Gy. Five-year OS favored concurrent therapy (27% vs. 9%). Myelosuppression was greater among patients in the concurrent arm, but treatment-related mortality was less than 1% in both arms.[24]

In the second trial, 610 patients were randomly assigned to sequential chemotherapy with cisplatin and vinblastine followed by 60 Gy of radiation therapy, concurrent chemotherapy or concurrent chemotherapy with cisplatin and vinblastine with twice-daily radiation therapy. Median and-4 year survival were superior in the concurrent chemotherapy with daily radiation therapy (17 mo vs. 14.6 mo and 21% vs. 12% for sequential regimen [P = .046]).[25] Two smaller studies also reported OS results that favored concurrent over sequential chemotherapy and radiation, although the results did not reach statistical significance.[26,27][Level of evidence: 1iiA]

Meta-analysis of three trials of concurrent versus sequential treatment (711 patients) indicated a significant benefit of concurrent over sequential treatment (RR = 0.86; 95% CI, 0.78–0.95; P = .003). All studies used cisplatin-based regimens and once-daily radiation therapy.[22] More deaths (3% OS rate) were reported in the concurrent arm, but this did not reach statistical significance (RR = 1.60;CI, 0.75–3.44; P = .2).There was more acute esophagitis (grade 3 or worse with concurrent treatment (range = 17%–26%) compared to sequential treatment (range = 0%–4%; RR= 6.77; P = .001). Overall, the incidence of neutropenia (grade 3 or worse) was similar in both arms.

Several small series have reported that reduction in fluorodeoxyglucose-positron emission tomography (FDG-PET) after chemotherapy, radiation therapy, or chemoradiation therapy correlate with pathological complete response and favorable prognosis.[22,25-31] Series have used different timing of assessments, positron emission tomography (PET) parameters, and cutpoints to define PET response. Reduction in maximum standardized uptake value (SUV) of more than 80% predicted for complete pathological response with a sensitivity of 90%, specificity of 100%, and accuracy of 96%.[32] Median survival after resection was greater for patients with tumor SUV values of less than 4 (56 mo vs. 19 mo).[31] Patients with complete metabolic response following radiation therapy were reported to have median survivals of 31 months versus 11 months.[33]. PET may be more sensitive and specific than the CT scan in assessing response to induction therapy. Optimal timing imaging remains to be defined; however, one study suggests that greater sensitivity and specificity of PET is achieved if repeat imaging is delayed until 30 days after radiation therapy.[32]

Radiation therapy may be effective in palliating symptomatic local involvement with NSCLC, such as tracheal, esophageal, or bronchial compression; pain; vocal cord paralysis; hemoptysis; or superior vena cava syndrome. (Refer to the PDQ summary on Cardiopulmonary Syndromes for more information.) In some cases, endobronchial laser therapy and/or brachytherapy has been used to alleviate proximal obstructing lesions.[34] A systematic review identified six randomized trials of high-dose rate brachytherapy (HDREB) alone or with external-beam radiation therapy (EBRT) or laser therapy.[35] Better overall symptom palliation and fewer retreatments were required in previously untreated patients using EBRT alone.[35][Level of evidence: 1iiC]. HDREB did provide palliation of symptomatic patients with recurrent endobronchial obstruction previously treated by EBRT, providing it is technically feasible. Although EBRT is frequently proscribed for symptom palliation, there is no consensus about when the fractionation scheme should be used. Although different multifraction regimens appear to provide similar symptom relief, [36-41] single-fraction radiation may be insufficient for symptom relief compared with hypofractionated or standard regimens, as evidenced in the NCIC Clinical Trials' Group trial NCIC-CTG-SC15.[38][Level of evidence: 1iiC] Evidence is available of a modest increase in survival in patients with better PS given high-dose radiation therapy.[36,37][Level of evidence: 1iiA]

Treatment options for patients with unresectable disease:

1. Surgery followed by adjuvant cisplatin-based combination chemotherapy for patients incidentally found to have occult N2 disease following complete resection.
2. Chemoradiation therapy for patients with stage IIIA-N2 disease.
3. Radiation therapy alone for patients medically unfit for combined modality therapy.

Superior sulcus tumors (T3, N0 or N1, M0)

NSCLC of the superior sulcus, frequently termed Pancoast tumors, occurs in less than 5% of patients.[42,43] Superior sulcus tumors (SST) usually arise from the apex of the lung and are challenging to treat because of their proximity to structures at the thoracic inlet. At this location, tumors may invade the parietal pleura, chest wall, brachial plexus, subclavian vessels, stellate ganglion, and adjacent vertebral bodies. However, Pancoast tumors are amenable to curative treatment, especially in patients with T3, N0 disease.

Adverse prognostic factors include the presence of mediastinal nodal metastases (N2 disease), spine, or subclavian-vessel involvement (T4 disease), and limited resection (R1 or R2).

While radiation therapy is an integral part of the treatment of Pancoast tumors, variations in dose, treatment technique, and staging that was used in various published series make it difficult to determine its effectiveness. In the preoperative setting, a dose of 45 Gy over 5 weeks is generally recommended, while a dose of approximately 61 Gy is required when using definitive radiation therapy as the primary modality.[42,43] Small retrospective series of radiation therapy of patients who were only clinically staged have reported 5-year survival rates of 0% to 40% depending on T stage, total radiation dose, and other prognostic factors. Induction radiation therapy and en-bloc resection was shown to be potentially curative. Retrospective case series have reported complete resection was achieved in only 64% of tumor stage (T) 3, nodal stage (N) 0, and 39% of T4, N0 tumors.[44]

Two large, prospective, multicenter phase II trials have evaluated induction chemoradiation therapy followed by resection.[42,45] In the first trial (SWOG-9416), 110 eligible patients were enrolled with mediastinoscopy negative, clinical T3–4 N0–1 tumors of the superior sulcus.[46] Induction treatment was two cycles of etoposide and cisplatin with 45 Gy of concurrent radiation therapy. The induction regimen was well tolerated and only five participants had grade 3 or higher toxic effects. Induction chemoradiation therapy could sterilize the primary lesion. Induction therapy was completed by 104 (95%) patients. Of 95 patients eligible for surgery, 88 (80%) underwent thoracotomy, two (1.8%) died postoperatively, and 83 (76%) had complete resections. Pathologic complete response or minimal microscopic disease was seen in 61 (56%) resection specimens. Five-year survival was 44% for all patients and 54% after complete resection, with no difference between T3 and T4 tumors. Pathologic complete response led to better survival than when any residual disease was present (P = .02). Disease progression occurred mainly in distant sites.

In the second trial, 75 patients were enrolled and treated with induction therapy with mitomycin C, vindesine, and cisplatin combined with 45 Gy of radiation therapy.[45] Fifty-seven patients (76%) underwent surgical resection, and complete resection was achieved in 51 patients (68%). There were 12 patients with pathologic complete response. Major postoperative morbidity, including chylothorax, empyema, pneumonitis, adult respiratory distress syndrome, and bleeding was observed in eight patients. There were three treatment-related deaths, The disease-free and OS rates at 3 years were 49% and 61%, respectively; at 5 years, they were 45% and 56%, respectively.[45][Level of evidence: 3iiiDi]

Treatment options for patients with superior sulcus tumors:

1. Radiation therapy and surgery.
2. Radiation therapy alone.
3. Surgery alone (selected cases).
4. Concurrent chemotherapy with radiation therapy and surgery.
5. Clinical trials of combined modality therapy.

Chest wall tumor (T3, N0 or N1, M0)

Selected patients with bulky primary tumors that directly invade the chest wall can obtain long-term survival with surgical management provided that their tumor is completely resected.

Treatment options for patients with chest wall tumors:

1. Surgery.[47,48]
2. Surgery and radiation therapy.
3. Radiation therapy alone.
4. Chemotherapy combined with radiation therapy and/or surgery.

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

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

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