Stage IB non–small-cell lung carcinoma (NSCLC) represents a subset of early-stage, resectable NSCLC, usually treated with curative intent, but with historically modest 5-year survival rates ranging from 40% to 67% with surgical resection alone.[1,2] Disappointingly, modern adjuvant chemotherapy trials including stage IB patients have shown little evidence of chemotherapeutic benefit. In the Adjuvant Navelbine International Trialist Association (ANITA) trial, for example, the 5-year survival rate was 64% with surgery alone vs 62% with adjuvant chemotherapy. Why is there such a wide range of results, and why does this subset of early-stage cancer patients have such a disappointing survival? As is often the case, the answer is likely multifactorial.
We hypothesize that considerable heterogeneity within the current stage IB category accounts for both the wide spectrum of results and relatively modest prognosis after therapy. With increased understanding of the molecular genetics of NSCLC, it has become more apparent that differences in the underlying cancer biology in individual patients account for a significant amount of the heterogeneity seen within any stage subset, especially one as broad as the IB category. As a distinct category within the tumor-node-metastasis (TNM) staging system for NSCLC, IB has long been under attack for being too broad, encompassing a wide range of tumor sizes (any tumor > 3 cm) and considerable variability in prognosis.[4-6]
Finally, it cannot be overemphasized that the stringency of preoperative and intraoperative staging greatly influences the accuracy of labeling NSCLC as stage IB, whether clinically or pathologically. Lack of positron-emission tomography/computed tomography (PET/CT) scan data, overinterpretation of increased standard uptake value (SUV) on PET/CT scan (false-positives), as well as lack of or incomplete nodal sampling/dissection at the time of surgery all result in inaccurate staging of some patients.
Herein, we review the available data regarding adjuvant chemotherapy following surgically resected stage IB NSCLC, framed within the context of present and future proposed definitions of this diagnosis. We discuss limitations of the current staging system and how this contributes to the mixed results seen with adjuvant treatment. Lastly, we present a perspective regarding current treatment options for stage IB NSCLC and review planned clinical trials for stage I disease designed to exploit new pharmacogenomic findings.
Current Criteria for Stage IB NSCLC
The most recent iteration of the staging system for NSCLC is the TNM International Staging System formulated in 1997. As defined, stage IB represents T2, N0, M0 disease, indicating T2 for the tumor size/characteristic descriptor, N0 for negative nodes, and M0 for no evidence of metastasis. T2 denotes a primary tumor > 3 cm, any size tumor involving the visceral pleura, or any size tumor causing atelectasis extending to the hilum but not involving the whole lung. There is no upper limit on size. If the tumor is within the airway, it must not be within a lobar bronchus or more proximal, and > 2 cm from the carina.
The heterogeneity encompassed by this definition is demonstrated by the following comparative example: A 1-cm tumor detected on screening chest CT that involves the visceral pleura is designated stage IB, as is a 12-cm primary tumor with lobar collapse discovered on chest x-ray because of signs and symptoms of pneumonia. Both of these tumors are defined as IB, therein delineating one of the confounding issues with the current staging system, which influences the range of prognoses associated with this stage.
Proposal for Revised Criteria for Stage IB
Recently, the International Association for the Study of Lung Cancer (IASLC) proposed a modification of the current staging system, and preliminary recommendations have been presented. Analysis of over 18,000 patients in an international database revealed five distinct cutoff points in the absolute size of the primary tumor (in pathologically staged, node-negative patients) that correlated with survival (Figure 1). Note the 58% 5-year survival rate in patients with a tumor > 3 cm but < 5 cm vs a 35% 5-year survival in patients with a tumor > 7 cm.
A summary of proposed T descriptor changes are shown in Table 1. Note the change in stage for tumors > 5 cm but ≤ 7 cm, from IB to IIA (the new T2b, N0, M0), and for tumors > 7 cm, from IB to IIB (the new T3, N0, M0). Adoption of the proposed changes in the T descriptor would appear to be a step forward in risk stratification for prognosis. Whether these changes would also assist in predicting potential benefit from adjuvant chemotherapy remains to be seen, although there is precedent for such a relationship, even within the currently defined T descriptor for stage IB, as discussed below.
Interestingly, the proposed changes to the IB stage subset do not address the clinical correlation of visceral pleural involvement independent of the size of the tumor or atelectasis, possibly because this detail has not been sufficiently delineated in the database. Relevant literature is divergent regarding the association between visceral pleural involvement and survival, with some investigators reporting that outcomes are dictated more by the size of the primary tumor and other parameters.
Other Factors Related to Heterogeneity Within Stage IB
As noted above, even within a given subset of T descriptors, individual cancers can differ greatly in regard to natural history, with divergent biologies conferring either an indolent course without distant metastases or an aggressive clinical course associated with early distant spread. It has become increasingly apparent that the TNM staging system reflects merely one component of a multifactorial process dictating the likelihood of survival in an individual patient. While it has long been known that specific features such as poor differentiation, presence of lymphovascular invasion, and other variables[6,10,11] portend a worse prognosis in individual patients with NSCLC, it is understandable that clinicians have been reluctant to use this information to alter treatment recommendations outside of those specified by TNM status.