Role of Adjuvant Therapy in Resected Stage II/IIIA Non-Small-Cell Lung Cancer

The first part of this article began an exploration of adjuvant therapy for completely resected (margin-negative) stage II/IIIA (node-positive) non-small-cell lung cancer (NSCLC). Using an evidence-based approach, the review sorted though key studies on the role of adjuvant treatment, focusing primarily on randomized trials of postoperative radiotherapy and postoperative chemotherapy, as well as two large meta-analyses—the postoperative radiotherapy (PORT) meta-analysis and the NSCLC Cooperative Group meta-analysis. The second part of this article will describe several studies evaluating the role of adjuvant chemoradiation, and will address currently active phase III trials of adjuvant therapy in this setting. Part 2 will conclude with a discussion of future strategies for the adjuvant treatment of NSCLC.

Adjuvant Chemoradiation

Only a few studies have assessed the role of adjuvant chemoradiation in the phase III setting.

Lung Cancer Study Group Trial

The Lung Cancer Study Group (LCSG)-791 trial compared split-course radiotherapy (2,000 cGy in five fractions × 2 separated by 3 weeks) and concurrent CAP chemotherapy (cyclophosphamide, doxorubicin(Drug information on doxorubicin) [Adriamycin], cisplatin(Drug information on cisplatin)) to radiotherapy alone.[1] This study focused on patients with an incomplete resection, defined as either tumor in the highest resected mediastinal node or the presence of a positive surgical margin. Most patients (N = 151) had stage III disease (119 had pN2 disease), 10 had stage II, and 3 had stage I. As in the previous LCSG study,[2] CAP was administered every 4 weeks for 6 months (with the first two cycles administered on day 1 of each radiotherapy course).

The chemoradiation group experienced a nonsignificant improvement in median survival (20 vs 13 months) but a significant improvement in median time to recurrence (14 vs 8 months, P = .004).[3] Analysis of failure patterns showed a significant decrease in distant metastases in the chemotherapy arm (P = .01). Subset analysis demonstrated a slight advantage for patients with pN2 disease who received both radiation and chemotherapy. However, with further follow-up, the survival curves converged at about 2.5 years.

Memorial Sloan-Kettering Trial

A study at Memorial Sloan-Kettering Cancer Center randomized 72 patients with pathologic T1-3, N2 (stage IIIA) NSCLC to postoperative radiotherapy vs radiotherapy and chemotherapy with vindesine(Drug information on vindesine) and cisplatin.[4] No significant differences were found in overall survival (16.3 months for radiotherapy plus chemotherapy vs 19.1 months for radiotherapy alone, P = .42) or time to progression (9.2 vs 9.0 months, respectively, P = .35).

French Trial

In a trial from France,[5] 267 patients with resected NSCLC were randomized to postoperative radiotherapy alone (6,000 cGy in 6 weeks) vs three cycles of chemotherapy (cycles 1 and 3: doxorubicin, vincristine, cisplatin, lomustine(Drug information on lomustine); cycle 2: vincristine, cisplatin, cyclophosphamide(Drug information on cyclophosphamide)) followed by radiotherapy. Most patients (N = 189) had stage III disease, 70 had stage II, and 8 had stage I.

There were no significant differences in overall survival or disease-free survival. Although the analysis was not stratified by stage, among the 137 patients who were pN2, a significant improvement in both survival and disease-free survival was observed in the chemoradiation group (P = .003 and P = .002, respectively), apparently due to a decreased incidence of metastases (P = .003).[5]

Intergroup Trial 0115

Perhaps the biggest setback to the use of adjuvant chemoradiation came with the results of Intergroup Trial 0115 (E-3590). In this large randomized trial,[6] 488 patients who had undergone complete resection of stage II and IIIA NSCLC, as well as a thorough mediastinal lymph node sampling or dissection, were randomized to receive either four cycles of monthly cisplatin (60 mg/m² on day 1) and etoposide(Drug information on etoposide) (120 mg/m² on days 1 to 3) administered concurrently with thoracic radiotherapy vs radiotherapy alone. Radiotherapy on both arms consisted of standard fractions (180 cGy) to a total dose of 5,040 cGy. An additional 1,080 cGy in six fractions was administered to nodal levels in which extracapsular extension was documented.

With a median follow-up of 44 months, the median survival was 39 months in the radiotherapy arm vs 38 months in the combined-modality arm (P = .56). An important finding on multivariate analysis was that survival was significantly influenced by extent of lymph node involvement (multiple vs single), type of lymph node dissection (sampling vs complete), age (60 or more vs < 60), and histology (other vs squamous). The authors concluded that postoperative chemoradiotherapy with cisplatin and etoposide does not prolong survival in patients with completely resected stage II/IIIA NSCLC compared to postoperative radiotherapy alone.

Potential caveats in interpreting this negative trial relate to the relatively high rate of ineligible patients (23%) and the relatively low rate of compliance with all the planned chemotherapy (69%). It is interesting to note that patients without evidence of K-ras mutations appeared to benefit from the addition of chemotherapy to radiotherapy (median survival: 42 vs 25 months), P = .066 on multivariate analysis.[7] This suggests that the underlying problem may not be the lack of effective adjuvant therapies, but rather the difficulty in properly selecting patients who truly benefit from these treatments.

German Trial

Yet another recent randomized trial further corroborates the lack of benefit of chemotherapy in addition to radiotherapy in the adjuvant setting.[8] In this study, patients with resected pN2 disease were randomized to either radiotherapy alone (50 Gy in 5 weeks) or chemotherapy with cisplatin, 75 mg/m² on day 1, plus ifosfamide(Drug information on ifosfamide) (Ifex), 1.5 g/m² on days 1 to 4, for three cycles every 4 weeks followed by the same radiotherapy. An interim analysis showed a median overall survival of 34 months and a 3-year survival rate of 46%, with no differences between the groups (P = .7).

NSCLC Cooperative Group Meta-analysis

Seven trials (807 patients) included in an NSCLC Cooperative Group meta-analysis randomized patients with resected NSCLC to surgery plus radiotherapy vs surgery plus radiotherapy plus chemotherapy. Six of these trials used a cisplatin-based regimen.[9] The total planned doses of radiation therapy ranged from 4,000 cGy in 10 fractions to 6,500 cGy in 33 fractions. The meta-analysis demonstrated a hazard ratio of 0.94, or a 6% reduction in the risk of death, favoring the chemotherapy arm, which translated into a 2% absolute benefit at 5 years but was not statistically significant.

Summary of Evidence-Based Data

The role of adjuvant therapy following a complete resection for stage II/IIIA NSCLC remains controversial. To date, there is no convincing evidence that any therapy consistently improves survival in the adjuvant setting. Thus, observation remains a viable alternative for such patients. Postoperative radiotherapy has been associated with a significant improvement in local control, particularly in patients with pathologic N2 disease. Several studies suggest that the pN2 subset may also have an improvement in recurrence-free survival. Patients with pathologic N0 disease (with negative margins) have a low risk of locoregional recurrence and, therefore, should not be offered postoperative radiotherapy

The benefit-risk ratio of adjuvant radiotherapy in the setting of pathologic N1 disease appears to be intermediate. Other factors may help in making treatment recommendations in this situation. For example, Yano et al[10] reported a 5-year survival of 40% for patients with hilar N1 disease, compared to 65% for those with lobar N1 disease (P = .014). As the survival for patients with lobar N1 disease approaches that of patients with pN0 disease, the benefit of postoperative radiotherapy is likely small in this group of patients. In the future, detection of lymph node micrometastases using immunohistochemical or molecular methods may be instrumental in further selecting which patients will benefit most from adjuvant therapies.[11]

If postoperative radiotherapy is administered, it should be done in the context of CT-based treatment planning with careful attention to the radiotherapy technique, including dose, fractionation, and volume. The most commonly used regimen in this country is 5,000 to 5,040 cGy in 25 to 28 fractions. The use of posterior spinal cord shields must be avoided. Special care should be taken to limit the amount of normal lung radiation, particularly on the contralateral side. Thus, lateral radiation fields should not be utilized. Similarly, the dose and volume of heart radiation should be minimized.

Only patients with adequate performance status and pulmonary function (generally FEV1 > 1 liter) after surgery should be considered for postoperative radiotherapy. The role of adjuvant chemotherapy (with or without radiation therapy) is less clear. Chemotherapy, at this time, should be offered to patients in appropriate clinical trials.