Non-Small-Cell Lung Cancer -- Stalemate or Progress? The New England Journal of Medicine -- October 26, 2000 -- Vol. 343, No. 17
Lung cancer is a major health problem, and each year the overall rate of death from this tobacco-inflicted disease increases. In a few countries, including the United States, the death rate has decreased slightly, reflecting changing attitudes toward cigarette smoking. Non-small-cell lung cancer, which includes adenocarcinoma, squamous-cell carcinoma, and large-cell carcinoma, accounts for 75 to 80 percent of all new cases of lung cancer; the remainder are due to small-cell lung cancer. In patients with non-small-cell lung cancer, the possibility of cure depends mainly on their suitability for surgical resection. Unfortunately, at the time of diagnosis, only about 30 percent of patients with this cancer are candidates for curative surgical resection. Another 30 percent have locally advanced, inoperable disease, and the remaining 40 percent have confirmed metastatic disease. Most patients die within 12 months after receiving the diagnosis, because the disease is already advanced at the time of detection. Even among the patients who undergo curative resection, recurrent metastatic disease develops within five years in half. For all these reasons, almost 85 percent of patients with non-small-cell lung cancer are candidates for chemotherapy alone or in combination with surgery or radiotherapy. Despite the wide use of chemotherapy in patients with non-small-cell lung cancer, its value is controversial. Combinations that include cisplatin and one or two other agents are the most widely used. In the overall management of non-small-cell lung cancer, the use of adjuvant chemotherapy may be considered after curative surgical resection of stage I or II disease, chemotherapy may be administered preoperatively to patients with locally advanced (stage III) disease, a combination of chemotherapy and radiotherapy may be recommended for patients with locally advanced, inoperable (stage IIIB) disease, and chemotherapy alone may be recommended for metastatic (stage IV) disease. Only a few of the many published trials of adjuvant chemotherapy after curative resection have reported any meaningful survival benefit from the addition of chemotherapy. Indeed, some studies, including the one by Keller et al., which appears in this issue of the Journal, found that chemotherapy had no effect on survival. The use of adjuvant chemotherapy after curative resection should not be considered standard care. Over the past decade, several trials have evaluated the value of neoadjuvant chemotherapy for locally advanced non-small-cell lung cancer. This approach has several advantages. A response to chemotherapy may allow an otherwise unresectable tumor to be removed surgically, the early introduction of chemotherapy may eradicate micrometastases, and pathological assessment of the resected specimen after neoadjuvant chemotherapy allows a detailed assessment of the efficacy of the chemotherapy and provides information about the need for further chemotherapy after surgery. Many trials have reported rates of response to preoperative chemotherapy of 40 to 75 percent, rates of resectability of 60 to 85 percent, and rates of complete pathological response of 15 percent. On average, the median survival in these trials was 18 months, and the survival rates at 3 to 5 years ranged from 25 to 30 percent. As compared with radiotherapy alone (median survival, 12 to 14 months), preoperative chemotherapy appears to confer some survival benefit. However, the patients who were selected for this treatment usually had an excellent performance status, had no other coexisting medical conditions, and were relatively young. Because the numbers of patients enrolled in these trials were small (usually less than 60), firm conclusions about the value of neoadjuvant chemotherapy are difficult to make. Other options, such as chemotherapy followed by radiotherapy, instead of surgery, might be equally beneficial. Presently, neoadjuvant chemotherapy should be considered for younger patients with a good performance status, locally advanced disease, and few or no coexisting medical conditions. Almost 30 percent of patients with newly diagnosed non-small-cell lung cancer have locally advanced, inoperable disease. The standard care is usually radiotherapy, and the expected median survival is one year, although a few patients survive for five years. Since many recurrences after radiotherapy are both local (within the radiation field) and distant (metastatic), it seems reasonable to treat not only the primary tumor but also micrometastatic disease. Many randomized trials with large numbers of patients have compared radiotherapy alone with chemotherapy plus radiotherapy. Most of these studies (as well as several meta-analyses that included more than 3000 patients) reported improvements in median and two-year survival with combined chemotherapy and radiotherapy, but the effects of this approach on long-term survival and cure rates are less obvious. Patients with advanced metastatic non-small-cell lung cancer constitute the largest group of candidates for chemotherapy. Despite its widespread use, the benefits of chemotherapy in these patients are unclear. The prognosis in this group is grim: the median survival without cytotoxic treatment is less than six months, and even with treatment, cures are almost unheard of. Before chemotherapy is initiated in such patients, its effect on the quality of life must be considered. In the early 1990s, debate raged about whether any patient with stage IV non-small-cell lung cancer should receive chemotherapy. Today, however, in some countries most patients are offered some kind of chemotherapy. What evidence exists to support this practice? A 1995 meta-analysis of 52 randomized trials that included more than 10,000 patients showed that, as compared with the best supportive care, cisplatin-based chemotherapy was superior in all major comparisons. Further studies indicated that although the rates of response to chemotherapy were only 20 to 30 percent, 60 to 70 percent of patients had decreases in disabling symptoms, such as cough, hemoptysis, and dyspnea. These data led to a new optimism, but unfortunately they have not been substantiated in recent large randomized trials. For these reasons, it is easy to understand the lack of universal acceptance of the use of chemotherapy for all patients with advanced non-small-cell lung cancer. Combinations that include cisplatin are probably superior to the best supportive care in terms of survival and the quality of life. There is, however, no standard or best chemotherapy regimen. In randomized trials that compared the old standards (e.g., cisplatin and etoposide) with newer combinations (e.g., paclitaxel, docetaxel, gemcitabine, and vinorelbine), higher response rates and improved survival rates at one year were frequently observed with the newer agents, but survival was not always significantly prolonged. The selection of particular drugs or combinations may be influenced by their ease of administration, toxicity, the presence or absence of coexisting medical conditions, and financial costs. All patients should be informed of the potential benefits, limitations, and adverse effects before embarking on chemotherapy, and all suitable patients should be encouraged to participate in clinical trials (including trials of new agents), so that real progress can be made against non-small-cell lung cancer. Lung cancer is the most preventable of all common cancers. The elimination of cigarette smoking remains the best hope for reducing mortality from this disease. For former smokers and those who continue to smoke, new techniques for the early detection of the disease, when it is most curable, and methods for preventing lung cancer are promising developments. Knowledge of the molecular events during the early stages of lung cancer, such as alteration of the expression of the fragile histidine triad (FHIT) gene and the presence in sputum of cells with genetic abnormalities, offers possibilities for early diagnosis. The use of chemopreventive agents such as orally administered vitamins has been of limited value, but the development of an aerosolized route of delivery for these agents, which would allow uniform delivery of the agent to the entire pulmonary epithelium, may enhance our ability to control or even reverse early changes associated with lung cancer. Such developments could benefit patients at risk for lung cancer. Desmond N. Carney, M.D. |