Lung cancer final stage

Stage IIIa non-small cell lung cancer represents a relatively heterogeneous group of patients with metastatic disease to the ipsilateral mediastinal (N2) lymph nodes and also includes T3N1 patients. Presentations of disease range from apparently resectable tumors with occult microscopic nodal metastases to unresectable, bulky multistation nodal disease. Controversy abounds as to the optimal treatment of the various stage IIIA subsets, which is fueled by a lack of meaningful, large randomized trials. Multimodality therapy of some type appears to be preferable in stage IIIA patients.

Key words: adjuvant chemotherapy, adjuvant radiotherapy; chemotherapy; guidelines; lung carcinoma; neoadjuvant therapy; non-small cell lung cancer; pulmonary surgical procedures; radiation therapy

Abbreviations: CALGB = Cancer and Leukemia Group B; CAP = cyclophosphamide-doxorubicin-cisplatin; CHART = continuous hyperfractionated accelerated radiation therapy. ECOG = Eastern Cooperative Oncology Group; EORTC = European Organization for Research and Treatment of Cancer; HART = hyperfractionated accelerated radiation therapy; LCSG = Lung Cancer Study Group; MRC = Medical Research Council; NSCLC = nonsmall cell lung cancer; NSCLCCG = Non-Small Cell Lung Cancer Collaborative Group; PET = positron emission tomography; PS = performance status; SWOG = Southwest Oncology Group; UFT = uracil-tegafur

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The evidence-based guidelines that follow are written primarily to provide a succinct synthesis of the medical literature and provide specific treatment guidelines that can serve as a useful tool for the clinician who deals directly with locally advanced non-small cell lung cancer (NSCLC). Exhaustive detail about published trials will be avoided in order to make this a more readable and usable guide. In order to develop the following guidelines for stage IIIA disease, the authors reviewed 15 other published guidelines, 9 meta-analyses, 12 systematic reviews, and 80 primary articles on this topic, focusing on the most well-designed, peer-reviewed reports. Selected key references are included in the bibliography.

Based on the collected series of 5,230 patients with NSCLC seen in the period from 1975 to 1988 at the M.D. Anderson Cancer Center reported by Clifton Mountain in the 1997 revision of lung cancer staging criteria, (1) 30% of all patients have locally advanced disease at initial presentation. Of those, one third (10% of the total) have stage IIIA with ipsilateral N2 lymph node metastases, which in the United States would then encompass approximately 17,000 new patients yearly. This group forms perhaps the most therapeutically challenging and controversial subset of patients with lung cancer, with a published 5-year survival of only 23%. (1)

This border-zone subset of stage IIIA patients, which lies between the generally resectable stage I and II tumors and unresectable stage IIIB patients, has been the subject of a wide variety of clinical trials incorporating various combinations of chemotherapy, radiotherapy, and surgery. Unfortunately, most published studies have significant limitations since they are not randomized, lack rigorous pretreatment staging, or involve a significant lack of homogeneity in the study population, making interpretation of the results difficult. There are a few more rigorous randomized trials, which will be discussed subsequently, that suggest a combined modality approach may be beneficial in stage IIIA disease. The approach showing the greatest promise in selected patients employs initial treatment (induction or neoadjuvant therapy) with chemotherapy or chemoradiotherapy followed by surgery. Nevertheless, more widespread use of induction therapy followed by surgery for lung cancer has been used for only 7 years, and as a result there is little reliable data with larger patient groups. This lack of meaningful, larger, randomized data underscores the importance of enrolling patients in clinical trials whenever possible.

Since staging and treatment are so very interdependent, intraoperative staging with systematic mediastinal node sampling or dissection is critically important. Unless histologic conformation of mediastinal node status is obtained at the time of surgery, postoperative pathologic staging will be inaccurate, as will further treatment recommendations and the discussion of prognosis. Therefore, the standard of care in modern thoracic surgery dictates that mediastinal node sampling or dissection must be performed at the time of every lung resection for lung cancer.

Under the 1997 revised lung cancer staging system, (1) stage IIIA encompasses all tumors with ipsilateral mediastinal lymph node metastases (T1-3, N2). Also included in this stage are tumors with resectable chest wall involvement and hilar node metastases (T3N1), added primarily because of similar survival rates. However, the treatment recommendations and applicable clinical trials for T3N1 are the same as for stage II. Therefore, for the purposes of these current guidelines, T3N1 tumors are discussed in the preceding chapter on stage II tumors. The present chapter will deal only with N2 disease.

Nevertheless, the patients with stage IIIA (N2) tumors present substantial heterogeneity in clinical presentation, treatment, and prognosis. Therefore, for the purposes of generating rational treatment guidelines, we have chosen to classify N2 tumors into four subsets (Table 1), which have been published previously. (2) The subsequent discussion of the literature and treatment guidelines will be broken down into these subsets.

PREVIOUSLY PUBLISHED GUIDELINES

In drafting these evidence-based guidelines for stage IIIA NSCLC, the authors not only reviewed the literature of clinical trials and reviews, but also 15 sets of recently published, major lung cancer guidelines were considered. (3-17) In general, there were few real differences in the actual recommendations between guidelines in this area of lung cancer. Some of the previously published guidelines were consensus based entirely, while others (such as the current guidelines) followed the evidence-based format. Among the latter group of guidelines, there were only some minor differences, primarily in determining the strength of the evidence supporting the specific recommendations.

TREATMENT OF SPECIFIC PATIENT GROUPS

Incidental N2 Disease (Stage III[A.sub.1-2])

Despite careful preoperative staging including CT scan, positron emission tomography (PET), and mediastinoscopy, some patients will be found to have metastases to mediastinal N2 lymph nodes at thoracotomy. In some, metastatic nodal disease will be found as a surprise a number of days postoperatively on the final pathologic examination of the surgical specimen (stage III[A.sub.1]). In others, metastases will be found intraoperatively as an unexpected finding at thoracotomy with a frozen-section pathologic examination of mediastinal nodes (stage III[A.sub.2]). Unexpected nodal metastases in this setting are not that unusual. In the pre-PET scan era, one surgical series of 102 patients from the Brompton Hospital in London with no clinical evidence of mediastinal adenopathy at thoracotomy found 24% of patients had pathologically positive nodes. (18,19)

Surgery: Despite negative preoperative staging studies including mediastinoscopy, as many as one fourth of patients will be found at surgery to have occult N2 metastatic disease. (18,19) If only one nodal station is unexpectedly found to be involved with metastatic lung cancer at open thoracotomy, and all of the involved nodes are technically resectable and the primary tumor is also technically resectable, then the surgeon should proceed at that time with the planned lung resection along with a mediastinal lymphadenectomy. If a complete resection is not possible or there is multistation or bulky, unresectable extracapsular nodal disease, then the planned lung resection should be aborted. Although incomplete resection rarely results in long-term survival, collected results of surgery alone in stage IIIA (N2 disease) provides a 14 to 30% 5-year survival, with the best survival seen in cases with minimal N2 disease and complete resection. (20-27)

At least 27 to 36% of patients with metastatic disease to the mediastinal N2 nodes will not have involvement of the hilar or lobar lymph nodes. (28,29) If resection of clinically negative mediastinal lymph nodes is not performed at the time of lung resection, it is possible that occult, subclinical metastatic disease to the N2 nodes will be missed, which will provide inaccurate pathologic staging and may alter the clinical course.