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

For those who believe a role exists for adjuvant therapy following resection of stage II or IIIA non-small-cell lung cancer (NSCLC), the past few years have been disappointing. In 1998, the postoperative radiotherapy (PORT) meta-analysis published in the Lancet demonstrated a survival decrement with postoperative radiotherapy in patients with NSCLC.[1] The controversial results of this trial received widespread coverage in the media. In the Philadelphia area alone, headlines ranged from "Study Questions Radiation Therapy" in the Philadelphia Inquirer to the broad-based conclusion, "Radiation No Help in Lung Cancer," in the Philadelphia Daily News.

More recently, the Intergroup randomized trial (0115) published in the New England Journal of Medicine showed no survival advantage when adjuvant chemotherapy was added to radiotherapy.[2] Is it simply time to "give up" on adjuvant therapy in this setting?

This two-part review, which will conclude in next month’s issue, evaluates the role of adjuvant therapy in completely resected (margin-negative) stage II/IIIA (node-positive) NSCLC, using an evidence-based approach and primarily focusing on randomized trials and meta-analyses.

Defining the Problem

Of all patients presenting with NSCLC, only about 30% are eligible for complete resections.[3] Mountain and others have shown that patients with pathologic stage I NSCLC (T1-2, N0) have 5-year survival rates ranging from 60% to 70%.[4-6] Patients with pathologic stage II (T1-2, N1; T3, N0) disease have lower 5-year survival rates of 30% to 50%,[7] and for those with resected stage IIIA (T1-3, N2; T3, N1) disease, 5-year survival rates range from 10% to 30%.[8,9]

The majority of recurrences are distant metastases to bone, liver, or brain. Even in stage I NSCLC, Feld documented distant metastases as the first site of recurrence in 65% to 77% of patients.[10] Patients with resected stage II or IIIA tumors have a similar recurrence pattern, although with more locoregional recurrences.[11,12] To decrease the incidence of recurrent disease following curative resections, a variety of adjuvant therapies, including radiation and/or chemotherapy, have been studied.

Key Variables

Surgical Staging

Detailed and consistent intraoperative surgical staging is essential for accurately assessing the efficacy of adjuvant therapy. In 1997, the tumor-node-metastasis (TNM) staging system was modified (Table 1 and Table 2),[13] and stages I and II were divided into two subsets (IA: T1, N0 vs IB: T2, N0; IIA: T1, N1 vs IIB: T2, N1 or T3, N0). Any metastatic tumor deposits found in the ipsilateral lung (other than the primary tumor lobe) are now defined as M1 (rather than T4). The anatomic definitions of some of the intrathoracic lymph nodes were altered.[14] The minimum number of lymph node stations that should be resected or sampled during a right thoracotomy are levels 4, 7, and 10, and for a left thoracotomy, levels 5 or 6, and 7.

It is unclear whether mediastinal lymph node sampling vs a complete lymphadenectomy affects survival. So far, only one randomized trial has compared mediastinal lymph node sampling with complete lymphadenectomy and found no difference in survival,[15] although this trial in 182 patients was underpowered to show a small improvement in survival. The American College of Surgeons Oncology Group (ACOSOG) has initiated a randomized trial of mediastinal lymph node sampling vs complete lymphadenectomy during pulmonary resection in patients with N0 or N1 (less than hilar) NSCLC (protocol Z0030). The accrual goal is 1,000 patients, and the primary end point is survival.

Patients with ipsilateral mediastinal lymph node involvement (N2) comprise a heterogeneous group of patients, with 5-year survival rates after surgery alone ranging from 6% to 35%.[16] Sawyer et al demonstrated that the number of N1 and N2 lymph nodes, as well as the number of N2 nodal stations involved are important prognostic variables.[17] In a recent analysis of over 700 patients who underwent surgical resection of N2 NSCLC, Andre et al detected four negative prognostic factors on multivariate analysis: clinical N2 status, involvement of multiple lymph nodes, pathologic T3/T4 stage, and no preoperative chemotherapy.[18]

Systemic Staging

Prior studies have demonstrated the value of positron-emission tomographic (PET) scanning in staging the mediastinum, as well as for systemic disease.[19] Van Tinteren et al [20] assessed the ability of PET to reduce futile thoracotomies in 188 clinically staged I to III NSCLC patients randomized (prior to mediastinoscopy or thoracotomy) to a conventional work-up vs conventional work-up plus PET. Thoracotomy was considered futile in benign disease, exploratory thoracotomy, pathologic stage IIIA (N2)/IIIB/IV disease, or postoperative relapse within 12 months. After 1 year, there were 39 (41%) futile thoracotomies in the conventional work-up arm vs 19 (21%) in the conventional work-up plus PET arm—a relative reduction of 50%.

Many of the studies to be reviewed span a period of more than 30 years. PET scans were unavailable at the beginning of that period, as were computed tomography (CT) scans of the chest or brain. The potential benefit of adjuvant therapy in the past may have been diluted by inadequate staging modalities.

Molecular Staging

A relative unknown in adjuvant therapy relates to underlying biologic or molecular genetic prognostic factors, which simply are not available for most patients. Molecular-clinical correlative studies in patients undergoing resection for NSCLC have identified various markers with differing prognostic significance, such as p53, K-ras, Bcl2, HER2, and Ki-67 among others.[21-23] These studies suggest that profiles of multiple markers may be necessary to obtain the greatest predictive value.

Recently, Cox et al demonstrated the potential of such "molecular staging" in 168 patients with resected stage I-IIIA NSCLC.[24] Multivariate analysis identified independent poor prognostic factors, including high microvessel count (P = .002), matrix metalloproteinase (MMP)-9 (P = .009)—a factor facilitating tumor invasion—nodal status (P = .01), and tumor grade (P = .05). The expression of both epidermal growth factor receptor (EGFR) and MMP-9 was associated with a poor prognosis (P = .0001). While prospective, well-designed, studies are necessary to confirm the value of potential markers, this type of "molecular fingerprinting" may pave the way for patients at high risk for recurrence to be candidates for molecular-based therapies targeting specific pathways.

Technical and Quality Variations

Many technical details of radiotherapy need to be evaluated, such as beam energy, volume of tissue irradiated, total dose, dose per fraction, overall treatment time, and timing of treatment in relation to surgery. Similarly, important issues must be considered regarding the administration of chemotherapy—the specific chemotherapy agents employed, their mechanisms of action, and potential interaction with radiotherapy and compliance with the planned regimen. The quality of each study itself must also be assessed.

Adjuvant Radiation

Unlike systemic therapy, the primary goal of radiotherapy is that of local control. Most radiation oncologists consider a locoregional relapse rate of 15% high enough or more to warrant a recommendation for postoperative radiotherapy. The lack of a clear survival benefit does not necessarily negate the importance of enhancing local control.

Locoregional failure in the mediastinum following surgery alone can have devastating quality-of-life consequences, leading to airway obstruction, hemoptysis, dysphagia, and/or chest pain. The potential benefit of postoperative radiotherapy in the enhancement of local control must be weighed against its side effects and possible complications. The main acute side effects include fatigue, skin irritation, and radiation esophagitis. Subacute and chronic complications primarily include radiation pneumonitis, lung fibrosis, and possible cardiac damage.