Lesson 12, Volume 16—Stage IIIA Non-Small Cell Lung Cancer: Evaluating and Treating Patients With N2 Disease

By Aminah Jatoi, MD; and James R. Jett, MD

Objectives

1. Define N2 disease as it pertains to patients with non-small cell lung cancer.
2. Identify the pitfalls associated with staging lung cancer when N2 disease is suspected.
3. Discuss effective treatment strategies for patients with this stage of non-small cell lung cancer.
4. Estimate the 5-year survival rates without treatment for N2 disease.
5. Estimate the 5-year survival rates with treatment for N2 disease.

Key words

chemotherapy; non-small cell lung cancer; N2 disease; radiation; stage IIIA; surgery

Abbreviations

NSCLC = non-small cell lung cancer; PET = positron emission tomography

What is the optimal approach for evaluating patients with stage IIIA non-small cell lung cancer (NSCLC)? What is the best treatment—surgery? Radiation? Chemotherapy? Or a combination of the above? These questions are difficult to answer for lung cancer patients in general but are particularly vexing for patients with stage IIIA NSCLC. Different treatment approaches have been utilized, but none has yet been able to cure the majority of patients with this stage of lung cancer.

In this review, we focus on NSCLC patients with T1-3N2M0 tumors and exclude patients with T3N1M0 tumors. Patients with N2 disease, or tumor involvement of the ipsilateral mediastinal or subcarinal lymph nodes, do not do as well with cancer treatment. To illustrate this point, patients with T3N1 NSCLC achieve 5-year survival rates of 40% after surgical resection, whereas in patients with T1-3N2 tumors, a complete surgical resection is attained only 60% of the time and then, after resection, the 5-year survival rate is only 25%.¹ This disparity in survival, along with the fact that the majority of patients with stage IIIA NSCLC do, in fact, have N2 disease, has led us to concentrate this review on the practical management of patients with T1-3N2M0 NSCLC.

Natural History

Left untreated, T1-3N2M0 NSCLC is highly lethal. In a retrospective study published in 1994, Vrdoljak and others² provide data on the natural history of stage IIIA NSCLC. It is unusual for patients to undergo state-of-the-art tumor staging only to forgo antineoplastic treatment, and the investigators themselves concede that "it is difficult to explain why... patients... went untreated." There is no information in this report to suggest that these patients were debilitated or had other comorbidities that would preclude cancer treatment. A total of 17 patients in this study had either T2N2M0 or T3N2M0 NSCLC on the basis of detailed diagnostic workups, which included CT, bronchoscopy, and thoracentesis, when necessary. The median survival of the 9 patients with T2N2M0 tumors was 10 months, whereas the median survival for the 8 patients with T3N2M0 tumors was 7.25 months. By 18 months, there were no survivors. Such data, derived from modern staging techniques, provide a rare glimpse into the natural history of stage IIIA NSCLC and clearly demonstrate that without antineoplastic treatment, patients with this stage of cancer suffer an early death. These data also provide a crude benchmark to gauge the success of treatment in the absence of randomized controlled trials.

Staging

Over- or under-staging patients’ malignancies can drastically alter treatment approaches and possibly also alter patient outcome. In NSCLC, two potential pitfalls surround the staging of disease in patients with possible N2 disease (Fig 1). The first pitfall involves inaccurately over-staging patients based on CT scan findings. Most patients will have already undergone CT scanning by the time of a tissue diagnosis, but these scan results should not constitute the final word as to whether or not a patient with NSCLC has N2 disease. Multiple studies have demonstrated that CT yields false-positive rates that approach 40% in its ability to predict tumor involvement of lymph nodes.³

Figure 1. A generalized approach for evaluating patients with N2 disease.

A study by McLoud and colleagues³ illustrates this point. These investigators evaluated 143 patients with NSCLC, all of whom had undergone CT scanning of the chest and all of whom subsequently underwent mediastinoscopy. During mediastinoscopy, biopsies were taken from all accessible nodes in the upper and lower paratracheal groups and from the anterior subcarinal nodes. Patients with no evidence of lymph node involvement by mediastinoscopy subsequently underwent thoracotomy with a complete lymph node dissection to confirm mediastinoscopy findings. Lymph nodes were evaluated on CT scans for size (> 1 cm) and for the absence of calcification, and both criteria provided evidence of tumor involvement. Using these criteria, these investigators found that on a per-patient basis, the sensitivity of CT scans for detecting malignant lymph nodes was 64% and the specificity was 62%. Particularly noteworthy is the observation that two of six lymph nodes, which measured between 3.0 and 3.9 cm, did not show evidence of tumor involvement at either mediastinoscopy or thoracotomy with complete lymph node dissection. In other words, without mediastinoscopy, this small subgroup of patients with enlargement of mediastinal lymph nodes visible on CT scan might have been falsely assumed to have malignant mediastinal disease and might have been deprived of certain treatment options based on this false assumption.

As noted above, such high false-positive rates with CT scanning have been confirmed in other studies and underscore the importance of proceeding with mediastinoscopy or mediastinal lymph node sampling via bronchoscopy or endoscopic ultrasound, even when CT scan results suggest mediastinal lymph node involvement with tumor. Detailed sampling of lymph nodes with mediastinoscopy may have its limitations insofar as this procedure cannot be used to access posterior subcarinal, inferior mediastinal, aortopulmonary window, and anterior mediastinal nodes. Recent reports demonstrate the value of endoscopic ultrasound for sampling mediastinal lymph nodes that may not be accessible with mediastinoscopy.⁴ Nonetheless, mediastinoscopy continues to be an essential component of the staging workup when treatment decisions hinge upon whether or not mediastinal lymph nodes are involved with tumor.

Recently, positron emission tomography (PET) scanning has been used in NSCLC staging to assess mediastinal lymph node involvement. Initial studies have been relatively small, including fewer than 100 patients with only a handful of exceptions.^5-7 PET scanning may lead to false-positive findings in the presence of surrounding inflammation, especially that due to granulomatous disease from histoplasmosis or tuberculosis, and poor anatomical resolution around the tumor may make it difficult to discern whether increased uptake represents the primary tumor or adjacent malignant lymph nodes. It may also lead to false-negative findings in the mediastinum when tumors are low-grade and therefore less metabolically active, or when lymph node involvement with tumor is present only microscopically, that is, in foci < 7 mm in diameter. In our opinion, mediastinoscopy remains the method of choice for examining mediastinal lymph node involvement by tumor, and it should be utilized in patients with enlarged mediastinal nodes on CT scan, central tumors, or PET scans that show increased uptake in mediastinal nodes. In some cases, bronchoscopic biopsy of lymph nodes or endoscopic ultrasound with lymph node aspiration may serve as a less invasive method of sampling mediastinal lymph nodes.

The second pitfall involves inaccurately under-staging disease in patients who appear to have clinical stage IIIA NSCLC. A study by Grant et al⁸ demonstrates that clinical evidence of locally advanced NSCLC can be a harbinger for widespread malignant disease that becomes manifest on closer scrutiny. In this retrospective study, pretreatment CT scans of the abdomen and brain detected metastases in 13% of asymptomatic patients, and thus redefined the treatment approach. Although patients with stage I and II NSCLC are unlikely to demonstrate evidence of metastatic disease, the same is not true for patients who appear to have locally advanced disease. In general, it has been observed that approximately 15 to 30% of patients who appear to have locally advanced disease are found to have metastatic disease after further staging (see Fig 1).⁹ These rates suggest that if cancer treatment entails some degree of increased morbidity, as is often incurred with combined-modality treatment, imaging of the head, abdomen, and possibly the skeletal system is indicated.

Therapy

Single-Modality Treatment

Under such circumstances, surgery alone or radiation alone has resulted in the achievement of 5-year survival for small groups of NSCLC patients with N2 disease. With respect to surgery, Pearson et al¹⁰ have demonstrated what many clinicians up to this point had only assumed: Patients who undergo a complete resection of their cancer with clean margins do better than patients who undergo a partial resection. These investigators found that 41% of patients with tumor-negative mediastinoscopy findings—but with N2 disease at the time of resection—survived to reach the 5-year mark after a complete resection. At the same time, 15% of patients with tumor-positive mediastinoscopy findings went on to reach the 5-year mark after a complete resection of their cancer. In contrast, the percentage of patients with incompletely resected tumors who achieved 5-year survivals was 0% and 14%, respectively, with tumor-positive and tumor-negative mediastinoscopy findings.

These findings raise two important points. First, a small group of patients with N2 disease undergo a false-negative mediastinoscopy preoperatively and are subsequently found to have mediastinal lymph node involvement at the time of surgery. In this setting, an attempt at complete resection of the tumor is worthwhile, as a relatively reasonable survival advantage, in the range of 25 to 40% survival at 5 years, can be obtained with a complete resection, and the patient has already been subjected to a thoracotomy. Second, in the setting of a tumor-positive mediastinoscopy, an attempt at surgical resection without the use of any other treatment modality is not worthwhile. Improved 5-year survival rates appear to be attainable with other treatment approaches (see below) and roughly 40% of patients with malignant lymph nodes on mediastinoscopy are found at surgery to have unresectable cancers. In other words, 40% of patients with positive mediastinoscopy findings are subjected to a thoracotomy when another treatment approach would have spared the thoracotomy and resulted in what would appear to be superior or similar survival rates. Although surgery can cure some patients with N2 disease, this observation applies best to those patients who have minimal mediastinal lymph node involvement and completely resected tumors.

Can radiation as a single treatment modality also cure patients with N2 disease? Several studies suggest that radiation alone can cure a small percentage of patients who have locally advanced NSCLC with N2 disease. Most of these trials have administered at least 6,000 cGy of radiation, and for this reason, most radiation oncologists think that giving much less constitutes only palliative treatment. Dillman and others¹¹ reported 5-year survival rates in the Cancer and Leukemia Group B 8433 trial. In this trial, 6% of patients with locally advanced NSCLC were alive 5 years after receiving radiation alone, and similar findings have been reported by Perez et al.¹² Admittedly, this survival rate is modest, but it does suggest that radiation alone can result in cure in a very small percentage of patients with locally advanced NSCLC.

Combined-Modality Treatment

A large number of studies suggest that combined-modality treatment, ie, combining more than one treatment modality, improves outcomes compared with single-modality approaches. Multiple clinical trials have studied combination treatment for patients with locally advanced NSCLC; these studies have usually included large numbers of patients with N2 disease. Tested approaches include (1) radiation alone vs radiation plus chemotherapy and (2) chemotherapy plus surgery vs surgery alone. Previous studies have also examined preoperative radiation plus surgery vs surgery alone and have not found an advantage with the use of both treatment modalities.¹³ The fact that most patients with locally advanced NSCLC develop recurrent disease at distant sites suggests that chemotherapy plays a critical role in prolonging disease-free survival. Hence, to our knowledge, no ongoing trials examine approaches that do not include chemotherapy as part of the regimen. Taken together, the majority of studies point convincingly toward the use of combined-modality treatment with chemotherapy as part of this combination.

Some of the largest and best-planned studies have evaluated radiation alone vs radiation plus chemotherapy. Although many but not all of these studies suggest that radiation plus cisplatin-based chemotherapy provides improved clinical outcomes compared with radiation alone, the preponderance of data supports the use of both these treatment modalities in combination. In the study alluded to above, Dillman et al¹¹ examined this approach in 155 NSCLC patients with locally advanced disease. Patients were randomly assigned to receive cisplatin and vinblastine followed by radiation of 6,000 cGy vs radiation of 6,000 cGy alone. In a follow-up analysis, long-term survival was improved with the use of combined-modality treatment, with 6% of patients alive at 5 years with radiation vs 17% surviving after combined-modality treatment. In another trial, Jeremic and others¹⁴ examined hyperfractionated radiotherapy vs concomitant chemotherapy and radiation. Randomizing a total of 131 NSCLC patients with locally advanced disease, these investigators treated patients with either (1) 6,900 cGy of radiation given concomitantly with the chemotherapy agents carboplatin and etoposide or (2) radiation alone. The combined-modality treatment resulted in a survival advantage, with median survivals of 22 months in the combination-treatment group vs 14 months in the radiation-treated group. These two studies, as well as others,¹⁵ suggest that chemotherapy plus radiation provides a reasonable approach for the treatment of patients with locally advanced NSCLC.

Promising results such as these have spawned the question, "How should we combine radiation and chemotherapy?" Should these treatment modalities be given sequentially, as in the trial by Dillman et al,¹¹ or should they be given concomitantly? Furuse and colleagues¹⁶ addressed this issue by randomly assigning 320 patients to one of two treatment arms: concomitant vs sequential chemotherapy and radiation. The chemotherapy consisted of cisplatin, vindesine, and mitomycin C. Median survival was improved among patients who received concomitant treatment when compared with those who received sequential treatment: 16.5 months vs 13.3 months, respectively. Five-year survival rates were also better: 15.8% for concomitant treatment vs 8.9% for sequential treatment. At the same time, however, the investigators noted greater rates of toxicity, specifically myelosuppression, with concomitant therapy. This study suggests that concomitant chemotherapy and radiation may be superior to sequential treatment but should probably be reserved only for patients with good performance scores.

In addition to the combination of chemotherapy plus radiation, the combination of chemotherapy plus surgery has also been examined. Several studies have shown that adjuvant, or postoperative, chemotherapy does not improve outcome in patients with NSCLC. For example, Keller and others¹⁷ recently randomly assigned a group of NSCLC patients who had undergone complete resections of either stage II or IIIA cancers to one of two treatment arms: (1) radiation alone with 50.4 Gy, or (2) chemotherapy with cisplatin and etoposide given concomitantly with the same radiation dose. Studying a total of 488 patients, these investigators found that the addition of chemotherapy did nothing to prevent intrathoracic tumor recurrence or to prolong survival. Such results suggest that chemotherapy in the postoperative setting provides no advantage. Additionally, the benefit of adjuvant radiation in this setting has not been clearly defined.¹⁸ Studying 230 patients with either stage II or III squamous cell carcinoma of the lung in a randomized trial, the Lung Cancer Study Group found that postoperative mediastinal radiation reduced the rate of local tumor recurrence but did not significantly improve survival.¹⁹

In contrast to adjuvant chemotherapy, neoadjuvant, or preoperative, chemotherapy may be beneficial. Several randomized trials have been performed to examine whether preoperative chemotherapy improves surgical outcome, and the findings have suggested that it does. One of these studies is a small trial of 60 patients by Rosell and others.²⁰ These investigators found a median survival of 26 months in patients treated with chemotherapy and surgery vs 8 months for surgery alone, suggesting that further investigation of neoadjuvant chemotherapy should be undertaken. A randomized study by Roth and others²¹ drew similar conclusions with follow-up extending to 82 months.

Two questions often arise in the minds of patients and clinicians as they consider neoadjuvant treatment: (1) "Will the cancer grow while chemotherapy is given, and will we thus have to close the door on surgical options?" (2) "Is such treatment well tolerated?" In the trial by Rosell et al,²⁰ 60% of patients showed evidence of tumor shrinkage with chemotherapy. This high response rate is in keeping with the results seen in other neoadjuvant chemotherapy trials and, for inexplicable reasons, is at odds with the much lower response rates observed in the setting of metastatic disease. These high response rates provide further justification for studying a neoadjuvant chemotherapy approach for patients with locally advanced NSCLC. Second, the study by Rosell and others²⁰ demonstrated that neoadjuvant chemotherapy is well tolerated. Patients received three cycles of mitomycin C, ifosfamide, and cisplatin, and all patients randomly assigned to the combined-modality arm received all three cycles without major toxicity. Thus, these findings suggest that neoadjuvant chemotherapy can be given relatively safely to patients with locally advanced NSCLC.

Finally, if combining two treatment modalities appears to improve outcome among patients with locally advanced NSCLC, one might hypothesize that combining three treatment modalities—namely, chemotherapy, radiation, and surgery—may be even better. Although Keller and others¹⁷ recently demonstrated that adding both radiation and chemotherapy in the postoperative setting does relatively little, the question of whether preoperative treatment improves outcome remains unanswered. The purpose of the intergroup trial, INT-0139, a high-priority study sponsored by the National Cancer Institute, is to test the hypothesis that use of chemotherapy and radiation followed by surgery improves outcome compared with chemotherapy and radiation alone. Patients who have stage IIIA NSCLC with biopsy-proven N2 disease are randomly assigned to one of two treatment arms: (1) concomitant treatment with cisplatin and etoposide along with radiation to the chest, or (2) concomitant treatment with cisplatin and etoposide along with radiation to the chest, followed by surgical resection of the tumor. The primary aim of this trial is to determine whether progression-free survival, median survival, and long-term survival differ between the two groups. A similar trial is ongoing in Europe. Both these trials promise to play a major role in defining the standard of care for patients who have stage IIIA NSCLC with N2 disease.

Summary

The majority of patients who have stage IIIA NSCLC with N2 disease continue to die of their cancer, despite aggressive treatment. Despite this overall poor prognosis, however, subgroups of patients can and do survive for 5 years. Careful staging, followed by thoughtful consideration of the best treatment approach, is merited in the hope that patients may survive over the long term. Combined-modality treatment with radiation and chemotherapy is employed most often in this setting, although promising results have also been observed with neoadjuvant chemotherapy followed by surgery. The combination of chemotherapy, radiation, and surgery is currently under active investigation.

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