In recent years, the treatment of many patients with non-small-cell lung cancer (NSCLC) has evolved into a multidisciplinary effort combining the talents of medical oncologists, radiation oncologists, and thoracic surgeons. Prospective, randomized trials have demonstrated improved survival rates in patients with locally advanced disease who are treated with cisplatin(Drug information on cisplatin) (Platinol)-based induction chemotherapy prior to radiation therapy[1,2] or surgery.[3,4] However, interpretation of these and other studies and application of the findings to the management of an individual patient require a thorough understanding of prognostic factors and staging.
Weight loss, performance status, age, gender, serum lactate dehydrogenase level, and disease stage are all known prognostic factors for patients with NSCLC. Pulmonary function and the presence of significant heart, lung, or other medical disease must be carefully considered prior to initiating multimodality therapy. In general, multimodality trials have enrolled patients with good prognostic features who were eligible to receive high-dose cisplatin chemotherapy and undergo thoracic surgery.
The importance of rigorous staging cannot be overemphasized. Particular attention must be paid to the supraclavicular (N3) and cervical (M1) lymph node regions on examination. In addition to routine serum and hematologic testing, an assessment of cardiopulmonary function, including pulmonary function tests with spirometry and measurements of diffusing capacity and arterial blood gases, is required. All patients should undergo a CT scan of the chest and upper abdomen, including the adrenal glands.
The routine use of brain and bone scans in patients with clinical stage I or II disease is controversial, but these imaging studies should be performed if clinically indicated. Patients who appear to have stage III disease should routinely undergo brain and bone imaging, as there is a greater likelihood of metastatic spread in this group. In patients who appear to have locoregional disease spread on CT scan, further evaluation of the mediastinum via bronchoscopy and mediastinoscopy, mediastinotomy, fine-needle aspiration, or video-assisted thora- coscopy provides essential information for proper staging and treatment selection.
Stages I and II NSCLC
In a series of 598 resected stage I NSCLC patients from Memorial Sloan-Kettering Cancer Center, the 5-year survival rate was 82% in patients with
T1 N0 disease, as compared with 68% in patients with T2 tumors. Despite complete resection, 50% of the 62 patients who underwent wedge resection or segmentectomy had a recurrence.
This finding is similar to the results of the Lung Cancer Study Group (LCSG) trial, which randomized T1 N0 patients to lobectomy or limited resection (segmentectomy or wedge resection). This trial found a significant increase in local recurrence and a decreased survival rate following limited resection. Given these findings, it seems unwise to pursue thoracoscopic resection for patients with T1 N0 disease.
The rate of second primary cancers after resection of stage I NSCLC is very high; fully one-third of patients from the Memorial Sloan-Kettering series developed second primaries. Given these findings, resected stage I patients should be encouraged to participate in chemoprevention trials.
Patients with stage II (T1-2 N1) disease represent about 10% of all patients with NSCLC and have a 5-year survival rate of 39% following surgery. Because of the poor prognosis of patients with relatively early-stage disease, research has focused on adjuvant therapies.
Trials of postoperative adjuvant therapy for early NSCLC have yielded mixed results, although the majority of trials have been negative. A recent Japanese trial found that NSCLC patients (the majority of whom were stage I) randomized to receive oral tegafur(Drug information on tegafur) (Ftorafur) plus uracil for 1 year after surgery had improved survival compared to those who received no further treatment. Currently, the National Cancer Institute of Canada is conducting a trial comparing four courses of vinorelbine (Navelbine) and cisplatin to no additional treatment in patients with completely resected T2 N0 or T1-2 N1 NSCLC. In this study, tissue is also being collected to develop a large tumor bank. This should facilitate identification of important biologic prognostic factors that may allow for selection of appropriate candidates for adjuvant therapy in the future.
Induction chemotherapy with paclitaxel(Drug information on paclitaxel) (Taxol) and carboplatin(Drug information on carboplatin) (Paraplatin) is currently under investigation in the Bimodality Lung Oncology Team (BLOT) trial. This trial is ongoing at seven major cancer centers across the United States.* The protocol calls for perioperative chemotherapy (two induction and three postoperative cycles) for clinical T2 N0, T1-2 N1, or T3 N0-1 NSCLC. Eligible patients must have a negative mediastinoscopy. This is the first trial to employ induction chemotherapy for "early"-stage disease.
Given the potential morbidity of chemotherapy and the preponderance of negative data from the randomized adjuvant chemotherapy trials completed to date, "standard" treatment of stage I and II NSCLC remains surgery alone. Results of trials employing newer-generation chemotherapy regimens in the preoperative and postoperative setting are anxiously awaited.
Stage III NSCLC
As discussed by Greco and Hainsworth, patients with stage IIIA NSCLC are a very heterogeneous group. At the more favorable end of the spectrum are patients with T3 N0-1 disease. Following surgical resection, these patients have 5-year survival rates of 40% to 50% (N0) or 20% (N1). Many such patients were included in the randomized perioperative chemotherapy trials of Roth et al and Rosell et al.[3,4] Both of these trials found significantly improved survival rates among patients who received chemotherapy and surgery compared with those who received surgery alone.
The outcome for patients with "minimal N2" disease (intranodal involvement of a single ipsilateral mediastinal lymph node) found at thoracotomy depends on T-stage; patients who have T1 or T2 primary tumors fare better than those who have T3. Minimal N2 disease is relatively uncommon (10% to 20% of IIIa NSCLC) and is usually discovered at the time of thoracotomy. Patients with this presentation usually undergo resection that includes a complete mediastinal lymph node dissection and have a 5-year survival rate of 30%.
The optimal treatment of patients with multiple levels of N2 (nonbulky) nodal involvement is in evolution. It is clear that single-modality treatment with surgery or radiation alone affords little chance for long-term survival. Many phase II trials have demonstrated improved response, resection, and survival rates with induction chemotherapy or chemoradiotherapy before surgery. Other investigators have treated similar patients with chemotherapy and radiation given either concomitantly or sequentially (without surgery). The results of these trials have been strikingly similar, with most reporting long-term survival rates in the range of 20%.
At present, it is not known whether surgery or irradiation is the optimal "adjuvant" to chemotherapy or whether "trimodality" therapy is better than "bimodality" therapy. Moreover, the value of additional chemotherapy cycles after surgery or irradiation has not been established. It is noteworthy that patients who achieve a pathologic complete response following induction chemotherapy enjoy the best chance for long-term survival. Given that the majority of patients die of systemic disease, only improvements in systemic therapy will likely lead to meaningful increases in long-term survival.
Patients with multiple bulky ipsilateral nodes or extracapsular spread (the least favorable IIIA presentation) or those with contralateral mediastinal or hilar nodal disease, supraclavicular nodal involvement, or direct mediastinal invasion (IIIB disease) should be offered combined-modality therapy with chemotherapy and irradiation. Trials currently underway are exploring refinements in radiotherapy (dose delivery and fractionation), chemotherapy/radiation interactions (sequential vs concomitant) and newer chemotherapy combinations. To date, there is no evidence from randomized trials that radiation given concomitantly with chemotherapy yields improved survival in patients with NSCLC. However, there is an increase in treatment-related toxicity with this approach. Thus, unless future data prove otherwise, the concomitant use of chemotherapy and radiation therapy for stage III NSCLC is not recommended outside the context of a clinical trial.
Postoperative mediastinal irradiation has been shown to significantly reduce the risk of mediastinal relapse but does not have a measurable effect on survival in patients with resected, node-positive NSCLC. Studies of postoperative chemotherapy for stage III disease have shown no benefit on overall survival. The LCSG trials employing cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar), doxorubicin(Drug information on doxorubicin), and cisplatin chemotherapy after surgery did not show a significant improvement in overall survival.[12,13] Similarly, trials conducted at Memorial Sloan-Kettering Cancer Center and in Japan found no benefit of postoperative high-dose cisplatin and vindesine(Drug information on vindesine) (Eldisine) chemotherapy.
Finally, patients with malignant pleural effusions (T4) should not be considered for combined-modality therapy, as their prognosis mirrors that of patients with metastatic disease.
As reviewed by Greco and Hainsworth, a number of new chemotherapeutic agents that hold promise for the treatment of patients with stage IIIB and IV NSCLC have been identified recently. New chemotherapy combinations of paclitaxel/cisplatin, paclitaxel/carboplatin, and vinorelbine/cisplatin appear to be superior to etoposide(Drug information on etoposide) (Etopophos/VePesid)/cisplatin. Other combinations incorporating gemcitabine(Drug information on gemcitabine) (Gemzar) and topotecan(Drug information on topotecan) (Hycamtin) are now being tested. Incorporation of the "new generation" of chemotherapy into the therapy for NSCLC will hopefully lead to improved survival for all patients with this disease.