Stage III Lung Cancer: Two or Three Modalities? Review 1

September 1, 2006

Lung cancer is the leading cause of cancer mortality in the United States. A significant number of patients present with disease involving mediastinal lymph nodes. As survival after surgery alone for stage III disease is poor, radiation therapy and chemotherapy have been evaluated in the neoadjuvant and adjuvant settings to improve outcomes. The benefit of adjuvant chemotherapy in the subgroup of patients with N2 disease is uncertain. Small randomized trials enrolling patients with stage III disease have shown a benefit of neoadjuvant chemotherapy over surgery alone. Whether neoadjuvant chemotherapy is superior to adjuvant chemotherapy is under investigation. Furthermore, whether neoadjuvant chemoradiotherapy is superior to neoadjuvant chemotherapy is controversial, and few randomized studies comparing these approaches have been reported. Nevertheless, neoadjuvant chemoradiotherapy appears to be associated with higher rates of resection, higher rates of clearance of mediastinal nodal disease, and better local/regional control. The use of postoperative radiation therapy (PORT) has declined since the publication of the 1998 meta-analysis suggested a detriment in survival with this strategy. However, radiation techniques are improving and emerging data support the use of carefully delivered PORT. Finally, it remains unclear whether surgical resection offers an advantage over definitive chemoradiotherapy alone for stage III disease. In summary, locally advanced NSCLC remains a formidable challenge with few cures, and optimal treatment requires the careful use of surgery, chemotherapy, and radiation therapy.

Stage III disease accounts for 30% of all new non-small-cell lung cancer (NSCLC) cases per year in the United States. Stages IIIA (T3, N1; T1-3, N2) and IIIB (any T4 excepting malignant pleural effusion or any N3) encompass a heterogeneous population of patients with distinct substages for which widely differing opinions exist regarding the role of surgery, radiation therapy, and chemotherapy. In this issue of ONCOLOGY, Drs. Kelsey, Werner-Wasik, and Marks provide a timely discussion of controversies in the multimodality treatment of such patients and clarify the rationale, if not the role, of radiation therapy as part of definitive, neoadjuvant and adjuvant therapy.

Unresectable Stage III NSCLC

For "unresectable" stage III disease, radiation with chemotherapy is the standard of care. However, considerable debate regarding criteria for resectability exists. Even in patients with technically resectable disease, the question is often not whether their disease can be resected-because increasingly it can be-but whether surgical resection is in their best interest. Regardless, the results of treatment with surgery alone for most categories of clinical stage III disease are poor, with 5-year survival rates of 3% to 9%.[1,2]

Over the past 2 decades, combinations of treatment modalities (chemotherapy, radiation, surgery) have gradually improved survival rates. As the authors demonstrate in their Tables 1 and 2, the 5-year survival rates from phase III studies of unresectable stage III NSCLC treated with concurrent chemoradiotherapy now exceeds 20%. In this same vein, the encouraging results of the Southwest Oncology Group (SWOG) 9504 trial demonstrated a 5-year survival of 29% and a median survival of 26 months in patients with pathologic stage IIIB disease treated with radiation therapy given concurrently with cisplatin and etoposide followed by three cycles of consolidation docetaxel.[3,4]

Clearly then, combined-modality treatment with chemotherapy and definitive radiation therapy (doses of 60-66 Gy) can be expected to offer good-performance-status patients with N2 mediastinal nodes or stage IIIB disease a 20% to 30% 5-year survival rate. What then might be the value added by surgery in stage III disease?

Potentially Resectable Stage III NSCLC

Preoperative (neoadjuvant) chemotherapy or chemoradiotherapy has several theoretical advantages over postoperative use. These factors have led to several combined-modality studies employing various regimens of neoadjuvant chemotherapy or chemoradiotherapy prior to surgery (Kelsey et al's Tables 4 and 7).

Thus far, however, no phase III study has shown that the addition of surgery to chemoradiotherapy significantly improves survival compared to chemoradiotherapy alone for pathologically staged N2 disease.[5-7] In the Intergroup 0139 study, surgery did improve progression-free survival (22% vs 11%) in a statistically and clinically meaningful way. Although a trend toward improved overall survival at 5 years was observed (27% vs 20%), this difference was not statistically significant, in part due to an excess of treatment-related mortality in the surgical arm, especially in those undergoing right-sided pneumonectomy.

Certainly, surgery may benefit some patients with stage III NSCLC, but additional investigation is necessary to define these subsets. Based on the available data, most lung cancer investigators would agree that patients who should be excluded from a surgical approach include those requiring a pneumonectomy, those with bulky mediastinal N2 or N3 involvement, and the medically inoperable. Patients with limited N2 disease[2] and those achieving complete pathologic clearance of N2 nodes[8] might derive the most benefit from surgery following neoadjuvant therapy.

However, the optimal neoadjuvant therapy (chemotherapy or chemoradiotherapy) and the risk/benefit ratio of these approaches, especially for patients with limited N2 disease remain poorly defined. Currently, a North American Lung Intergroup trial, Radiation Therapy Oncology Group (RTOG) 0412/SWOG 0332, is evaluating the role of preoperative radiation combined with chemotherapy vs induction chemotherapy alone prior to surgery for the subset of stage III NSCLC patients with limited N2 disease.

As noted above, pathologic clearance of N2 nodes after induction therapy has been demonstrated to be an important prognostic factor. We agree with the authors' assessment that it remains unclear how much patients achieving pathologic N2 clearance after neoadjuvant therapy benefit from surgery. Would they have been cured with chemoradiotherapy alone? There is currently no universally accepted approach to reevaluating the mediastinum after induction therapy. Repeat mediastinoscopy, video-assisted thoracoscopy, 18F-fluorodeoxyglucose-positron-emission tomography (FDG-PET), and esophageal or transbronchial ultrasound are some methods that have been proposed, but none have been validated. The current RTOG/SWOG Intergroup study is evaluating FDG-PET for response after preoperative therapy and will hopefully provide some useful information.

Resected Stage III NSCLC

In this era of effective adjuvant chemotherapy, the authors eloquently readdress the rationale for adjuvant radiation therapy. Although a meta-analysis showed a survival detriment to postoperative radiation therapy for stage I/II NSCLC,[9] several studies performed in the modern era of radiation therapy do show a benefit in terms of local control (Table 5). The authors propose that the integration of postoperative chemotherapy may help reduce distant failure, in which case local control should gain importance in order to ultimately achieve cure (Figures 1 and 2).

To this end, a new generation of studies testing modern techniques of radiation therapy combined with chemotherapy for resected III patients seems warranted. The RTOG recently completed a phase II study of postoperative paclitaxel/carboplatin and radiation therapy (50.4-61.2 Gy), demonstrating a promising 3-year survival of 61% for stage II/IIIA NSCLC.[10] In patients with resected NSCLC demonstrating unsuspected microscopic N2 disease, SWOG is initiating a randomized phase II trial of postoperative chemoradiotherapy, given either sequentially or concurrently, to test feasibility and toxicity.

Update on Adjuvant Chemotherapy

The recent update of the Cancer and Leukemia Group B (CALGB) 9633 study at the American Society of Clinical Oncology annual meeting in 2006 has called into question the benefit of chemotherapy for patients with stage IB disease. The first interim analysis of this study demonstrated a 12% survival benefit (71% vs 59%). However, the updated results[11] show that the survival benefit at 5 years is no longer significant. Furthermore, subset analysis of the stage IB patient from the National Cancer Institute of Canada (NCIC) and Adjuvant Navelbine International Trialist Association (ANITA)[12] trials did not demonstrate a significant survival benefit. While it is clear that adjuvant chemotherapy provides a survival benefit for patients with stage II/IIIA disease, its role for stage IB remains to be defined.

Conclusions

In summary, careful staging is especially important to determining treatment decisions in stage III NSCLC, based on the heterogeneity of this patient population. Patients should undergo multidisciplinary evaluation to determine the most appropriate treatment approach. Those deemed surgically unresectable should receive a definitive chemoradiotherapy regimen, assuming adequate performance status and pulmonary function, and a low level of comorbidities. For those in whom a surgical approach is felt to be most appropriate, and in whom eligibility criteria are met, enrollment in the ongoing RTOG 0412/SWOG 0332 study is highly recommended. Only through such clinical research endeavors will current controversies be resolved.

-Samir Narayan, MD
-Royce Calhoun, MD
-David R. Gandara, MD

Disclosures:

Dr. Gandara has received a speaker honorarium from and is a member of the advisory board for Sanofi-Aventis.

References:

1. Martini N, Flehinger BJ: The role of surgery in N2 lung cancer. Surg Clin North Am 67:1037-1049, 1987.

2. Andre F, Grunenwald D, Pignon JP, et al: Survival of patients with resected N2 non-small cell lung cancer: Evidence for a subclassification and implications. J Clin Oncol 18:2981-2989, 2000.

3. Gandara DR, Chansky K, Albain KS, et al: Consolidation docetaxel following concurrent chemoradiotherapy in pathologic stage IIIB non-small cell lung cancer: S9504, a Southwest Oncology Group Study. J Clin Oncol 21:2004-2010, 2003.

4. Gandara DR, Chansky K, Gaspar LE, et al: Long term survival in stage IIIb non-small cell lung cancer (NSCLC) treated with consolidation docetaxel following concurrent chemoradiotherapy (SWOG S9504) (abstract 7059). J Clin Oncol 23(16S):635s, 2005.

5. Albain KS, Swann RS, Rusch VR, et al: Phase III comparison of concurrent chemotherapy plus radiotherapy (CT/RT) vs. CT/RT followed by surgical resection for stage IIIA(pN2) non-small cell lung cancer (NSCLC): Outcomes update of North American Intergroup 0139 (RTOG 93-09) (abstract 2497). J Clin Oncol 23(16S):624s, 2005.

6. Van Meerbeeck JP, Kramer G, Van Schil PE, et al: A randomized trial of radical surgery (S) versus thoracic radiotherapy (TRT) in patients (pts) with stage IIIA-N2 non-small cell lung cancer (NSCLC) after response to induction chemotherapy (ICT) (EORTC 08941) (abstract 7015). J Clin Oncol 23(16S):1095s, 2003.

7. Johnstone DW, Byhardt RW, Ettinger D, et al: Phase III study comparing chemotherapy and radiotherapy with preoperative chemotherapy and surgical resection in patients with non-small-cell lung cancer with spread to mediastinal lymph nodes (N2): Final report of RTOG 89-01. Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 54:365-369, 2002.

8. Albain KS, Rusch VW, Crowley JJ, et al: Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: Mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 13:1880-1892, 1995.

9. Postoperative radiotherapy in non-small cell lung cancer: Systematic review and meta-analysis of individual patient data from nine randomised controlled trials. PORT Meta-analysis Trialists Group. Lancet 352:257-263, 1998.

10. Bradley JD, Paulus R, Graham MV, et al: Phase II trial of postoperative adjuvant paclitaxel/carboplatin and thoracic radiotherapy in resected stage II and IIIA non-small-cell lung cancer: Promising long-term results of the Radiation Therapy Oncology Group-RTOG 9705. J Clin Oncol 23:3480-3487, 2005.

11. Strauss GM, Herndon JE, Maddaus MA, et al: Adjuvant chemotherapy in stage IB non-small cell lung cancer (NSCLC): Update on Cancer and Leukemia Group B (CALGB) protocol 9633 (abstract 7007). J Clin Oncol 24(18S):365s, 2006.

12. Douillard JY, Rosell R, Delena M, et al: ANITA: Phase III adjuvant vinorelbine (N) and cisplatin (P) versus observation (OBS) in completely resected (stage I-III) non-small-cell lung cancer (NSCLC) patients (pts): Final results after 70-month median follow-up. On behalf of the Adjuvant Navelbine International Trialist Association (abstract 7013). J Clin Oncol 23(16S):624s, 2005.