Adjuvant and Neoadjuvant Chemotherapy for Early-Stage Nonsmall Cell Lung Cancer

Rationale for Adjuvant Therapy

The use of adjuvant (postoperative) therapy for the treatment of various solid tumors is well established and is based on theoretical models and clinical observations. After complete resection, a patient’s tumor load should be nonexistent or minimal. Any residual neoplastic cells present in micrometastatic deposits should contain few clones resistant to chemotherapy or radiotherapy. Experimental and clinical data support the Gompertzian model of tumor growth and regression in most human solid cancers: when a tumor is present microscopically but is clinically undetectable, its growth rate should be at its highest. Therefore, although the numerical reduction of malignant cells induced by cytotoxic chemotherapy is small, the fractional cell kill from an effective dose of chemotherapy should be high.

The decision to use adjuvant therapy involves balancing the need to treat a large number of patients who may be cured by surgery alone against the need for additional systemic therapy to eradicate remaining cancer cells in only a subset of these patients. Thus, if survival is increased for 10% of patients, the other 90% are exposed unnecessarily, either because they did not need the adjuvant treatment or because adjuvant therapy was ineffective in eradicating residual disease. Because no tools exist that determine prospectively who will benefit from adjuvant therapy, it is very important to select a tolerable regimen and limit the length of treatment ( Fig. 51.1 ). In addition, careful pathologic staging enables better prediction of prognosis, facilitates patient selection, and permits comparison of treatment outcomes among trials.

The most appropriate treatment or regimen for the adjuvant setting has not been established. At a minimum, the chosen agent or agents should have proven activity in advanced disease and should be generally well tolerated. Thus, in the case of cytotoxic chemotherapy, a platinum-based doublet regimen should be selected, initiated sufficiently early after radical surgery, and administered for at least three or four cycles.

Role of Adjuvant Radiotherapy

Before effective chemotherapy regimens were established, postoperative thoracic radiotherapy was the preferred adjuvant treatment. Although radiotherapy may improve local–regional control, it is unlikely to reduce systemic recurrence. Use of radiotherapy has been evaluated in many retrospective and prospective studies. Data from nine of these studies (2128 patients) were included in the Postoperative Radiation Therapy (PORT) meta-analysis. The authors of this meta-analysis concluded that postoperative radiotherapy had a significant detrimental effect on survival, especially for patients with stage I and II disease. These results were confirmed by a Cochrane systematic review and meta-analysis in 2000 and substantially updated in 2005, which demonstrated that postoperative radiotherapy may have a significant adverse effect on survival (hazard ratio [HR], 1.18). The 18% relative increase in the risk of death is equivalent to an absolute detriment of 6% at 2 years (95% CI, 2% to 9%), reducing overall survival (OS) from 58% to 52%. Exploratory subgroup analyses indicate that this detrimental effect was most pronounced for patients with stage I or II disease. For patients with stage III N2 disease, there was no clear evidence of an adverse effect or potential benefit. This outcome is plausible because increased frequency of local–regional failure is associated with the bulky disease often seen in stage III NSCLC.

In most of the studies included in the PORT meta-analysis, patients were treated with older radiotherapy technology (e.g., cobalt 60) and outdated dosimetry, which are less effective than current treatment approaches, and the higher mortality rate in the radiotherapy groups can be attributed in part to an excess of deaths related to intercurrent disease. In a retrospective review, it was reported that use of new technologies and improved dosimetry for postoperative radiotherapy does not excessively increase the risk of death related to intercurrent disease. Another shortcoming of the PORT meta-analysis is that it failed to include sufficient data on mediastinal lymph node dissection, and, additionally, the surgical procedure varied substantially across studies and centers.

Using data from the United States Surveillance, Epidemiology and End Results (SEER) database, researchers evaluated the relation between survival and postoperative radiotherapy. Factors with a negative effect on OS were older age, T3 or T4 tumor stage, N2 node stage, male gender, fewer lymph nodes sampled, and a greater number of involved lymph nodes. In this study, the use of postoperative radiotherapy was associated with increased survival for patients with N2 disease, but not for patients with N1 or N0 disease.

The role of radiotherapy for patients with N2 disease remains unclear, as no definitive conclusions can be drawn from the available literature. The Lung Adjuvant Radiation Therapy trial in Europe, still ongoing, includes patients with N2 NSCLC who have had surgery, with or without adjuvant chemotherapy. Patients are randomly assigned to postoperative radiotherapy (54 Gy) or no radiotherapy, and it is hoped that results from this trial will define the role of adjuvant radiotherapy for patients with N2 NSCLC.

Early Studies of Adjuvant Chemotherapy

In the 1960s and 1970s, alkylating agents and nonspecific immunotherapies (e.g., levamisole and bacillus Calmette–Guerin vaccine) universally failed, and detrimental effects of these agents were occasionally reported. These drugs are now known to have very limited or no activity in advanced NSCLC. Subsequently, the use of cisplatin-based chemotherapy was extensively tested in all stages of resectable NSCLC. In all but one of these early studies, adjuvant therapy failed to show clinical benefit. Common flaws in the design of these trials were overestimation of the potential benefit of adjuvant chemotherapy, imbalance in relevant patient and treatment characteristics (for instance, the rate of incomplete mediastinal lymph node dissection), and unrealistic patient accrual goals. In addition, in most of the trials, chemotherapy dose delivery (total dose and dose intensity) was often inadequate, with only 50% of patients, on average, receiving the intended course of treatment. Given the toxicity of these regimens in the absence of good antiemetic supportive care and the lack of proven survival benefit from adjuvant therapy, physicians were reluctant to offer participation in adjuvant trials to their patients.

Nevertheless, the authors of a large meta-analysis, which included these trials, reported a 13% reduction in the risk of death with adjuvant cisplatin-based chemotherapy, a result of borderline significance ( p = 0.08). There was a 6% reduction in the risk of death among patients who received postoperative radiotherapy and cisplatin-based chemotherapy compared with patients who received postoperative radiotherapy only ( p = 0.46). In contrast, adjuvant chemotherapy with alkylating agents was shown to be significantly detrimental (HR, 1.15; p = 0.005).

These findings failed to have an effect on clinical practice because they were of only borderline significance and were based on several flawed studies. In addition, the heterogeneity of surgical procedures and the difference in the staging modalities limited the applicability of the results. Nevertheless, the findings strongly supported a potential role for adjuvant chemotherapy and the need for a large, well-designed confirmatory trial.