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A Randomized Trial of Postoperative Adjuvant Therapy in Patients with Completely Resected Stage II or IIIA Non-Small-Cell Lung Cancer

Reviewer: John J. Wilson, MD
The Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 23 de agosto del 2002

Authors: Keller SM, Adak S, et al.
Source: New England Journal of Medicine 2000; 343(17): 1217-22.

Background

In patients with surgically resected NSCLC (non-small-cell lung cancer), spread of the tumor to intrathoracic lymph nodes significantly worsens the prognosis for patients. Therefore, many of these patients receive post-operative therapy. The Lung Cancer Study Group found that radiotherapy, combined chemotherapy (cyclophosphamide, doxorubicin, and cisplatin), or both improve local control and disease-free survival, but not overall survival. Radiotherapy is considered to be standard therapy in patients with intrathoracic lymph-node metastases, but many physicians question the efficacy of postoperative chemotherapy. Therefore, the study authors investigated the benefits of postoperative chemotherapy by comparing radiation and chemotherapy compared to radiation alone after surgery in patients with Stage II and IIIa NSCLC.

Methods

• Study duration: 4/91-2/97
• Stratification by histology (squamous vs. others), weight loss in last 6 months (<5% vs. =5%), nodal involvement (N1 vs. N2), lymph node dissection (systemic sampling vs. complete dissection).
• Control group (radiation alone): 1.8 Gy fractions to total dose of 50.4 Gy
• Experimental group (concurrent radiation and chemo): radiation same as control, chemotherapy includes cisplatin 60mg/m2 d1, etoposide 120 mg/m2 d 1,2,3.
• Eligibility criteria: Stage IIA or III N1 or N2 NSCLC, complete resection by lobectomy or pneumonectomy, satisfactory post-op FEV 1, ECOG status 0 or 1, no multifocal bronchoalveolar tumors, no multilevel lymph node metastases/extranodal disease/contralateral mediastinal disease

Results

• 488 pts total: 242 RT alone, 246 RT and chemo.
• 69% completed chemo, 84% completed RT.
• Median follow up 44 months.
• Adverse effects: more common in RT/chemo - hematopoietic, esophagitis, nausea/vomiting.
• Treatment-related deaths: 3 in RT alone (radiation pneumonitis (2), esophagitis (1)), 4 in chemo/RT (sepsis (2), pneumonia (1), esophagitis (1)).
• Median survival: RT alone-39 months, RT/chemo-38 months. (p=0.56)
• No difference in survival based on stratification factors or sex, race, TNM staging, ECOG status, # operations/surgeon.
• Significant differences in overall and disease free survival based on: nodal involvement (single > multiple, 0S and DFS: p<0.001), type of lymph node dissection (complete > sampling, OS and DFS: p<0.001), histology (squamous > others, OS: p=0.02, DFS: p<0.001).
• No significant difference in recurrence rate (53% vs 56%), patterns of recurrence, median time to recurrence (30.4 vs. 26.1 months).

Author's Conclusions

• Unable to identify an advantage in adding concurrent chemotherapy to post-operative radiotherapy in preventing local recurrence or increasing overall survival.
• Combined chemotherapy and radiation caused more serious side effects than radiation alone.

Discussion

This study reports on a randomized trial investigating the benefits of adding concurrent chemotherapy onto postoperative radiotherapy for stage II and IIIA N1 or N2 NSCLC. There was no appreciable benefit in survival or recurrence with concurrent treatment, and there were more serious side effects as well. Over the past 20 years, nine phase three trials have been performed looking at adjuvant therapy (chemo, rads, or chemo/rads) in stage II or IIIA NSCLC patients. Six trials showed some benefit in disease free survival, but no benefit in overall survival. The other three trials used cisplatin followed by 6-12 months of a daily oral chemotherapeutic drug, and showed a survival benefit in the treatment group. These findings are of great interest but require validation before they are standard therapy. Also, since there is no clear evidence of a benefit with adjuvant chemotherapy in this group of patients, its use should be restricted to clinical trials. Of note, the median survival of both patient groups (38-39 months) was considerably longer than earlier studies in patients with similar stage cancers. This could be due to more accurate staging and/or better care of patients currently as compared to earlier. Survival seemed to be strongly associated with the type of lymph node dissection patients received, but there were no guidelines or explanations for who received what. Complete dissection was associated with improved survival, which could be due to better removal of metastatic lymph nodes, or it could be a marker for a more experienced/more thorough surgeon.