Paul A. Bunn, Jr, MD

In this article, we review the new developments in neoadjuvant therapy for lung cancer.

Almost 40% of patients with newly diagnosed small-cell lung cancer (SCLC) have disease confined to the ipsilateral hemithorax and within a single radiation port, ie, limited-stage disease. The median survival for this group of patients after treatment is approximately 15 months, with one in every four patients surviving 2 years. Current optimal treatment consists of chemotherapy with platinum/etoposide, given concurrently with thoracic radiation. Surgery may represent an option for very early-stage disease, but its added value is uncertain. Prophylactic cranial irradiation (PCI) is used for patients with limited-stage SCLC who have achieved a complete response following initial therapy, as it decreases the risk of brain metastases and provides an overall survival benefit. Newer targeted agents are currently being evaluated in this disease and hold the promise of improving current outcomes seen in patients with early-stage disease.

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. Before 1980, radiotherapy was considered the only real recourse in advanced disease. In 1995, a landmark meta-analysis of trials conducted in the 1980s and early 1990s demonstrated a survival benefit with platinum-based chemotherapy. Newer chemotherapy agents and improved supportive care measures have allowed more patients to benefit from chemotherapy with reduced toxicity. Concurrent platinum-based chemotherapy and radiotherapy has improved the survival in stage III disease, and recently chemotherapy has also demonstrated improved survival in resected early-stage disease. The majority of patients still present with advanced unresec disease for whom the prognosis remains poor, but for key subpopulations the outlook has improved markedly since the emergence of targeted therapies directed against the epidermal growth factor receptor and vascular endothelial growth factor receptor pathways. Patient selection and the incorporation of targeted therapies with cytotoxic chemotherapy are the focus of many ongoing studies, and there is an abundance of new agents undergoing clinical trials. Together, these developments have moved us away from the nihilism of 20 years ago into an era of unprecedented optimism in taking on the many remaining challenges of managing NSCLC in the 21st century.

Because of the high rate of distant disease recurrence, the 5-yearsurvival of patients who have undergone complete surgical resectionof localized non–small-cell lung cancer (NSCLC) is approximately 50%.Initial results from early studies of adjuvant postoperative chemotherapyreported an adverse effect of alkylating agent and older chemotherapyregimens on survival. Cisplatin-based combinations were the first toshow a survival advantage. A 1995 meta-analysis of these studies suggesteda 13% reduction in the hazard ratio for death (HR = 0.87), leadingto a 5% survival benefit at 5 years. Still, these trials involved limitednumbers of patients (N = 1,394), and the results failed to reach statisticalsignificance (P = .08). Of the five largest subsequent randomizedtrials of platinum-based adjuvant therapy, three showed a significantsurvival advantage. Although it is impossible to determine the reasonsfor the differing outcomes of these studies, several key features distinguishthem, and the data suggest that medically fit patients with resectedstage IB or II NSCLC should be offered chemotherapy with a platinum/new drug combination.

Quan and colleagues have providedan important and timelyreview on the treatment ofbrain metastases in patients with smallcell lung cancer (SCLC). We certainlyagree with the comments and viewsof the authors, but wish to emphasizeseveral aspects of central nervoussystem (CNS) metastases in SCLCpatients.

Several new antimetabolites, administered alone or in combination,are changing the therapeutic landscape for thoracic cancer. Two-drugcombinations involving these newer drugs are becoming the standardof care for non–small-cell lung cancer (NSCLC), largely due to improvementsin survival rates, time to disease progression, and responserates as well as an improved safety profile. Gemcitabine (Gemzar) haselicited considerable interest in this disease, as a combination partnerin chemotherapeutic regimens. Another promising agent is pemetrexed(Alimta), a folate-based inhibitor of thymidylate synthase. In preclinicaldevelopment, pemetrexed both alone and in combination with othercytotoxic agents has exhibited activity across a broad range of tumormodels, including NSCLC and mesothelioma. In clinical trials of patientswith NSCLC, pemetrexed has been an effective, well-toleratedagent that can be used as monotherapy or in combination with otheragents at full dose. In clinical trials of patients with mesothelioma, thecombination of pemetrexed and cisplatin demonstrated a significantimprovement in survival, response, and patient quality-of-life parameters.The principle toxicities of pemetrexed can be minimized by folateand vitamin B12 supplements.

In this issue of ONCOLOGY, Dr.John Eckhardt provides an excellentreview of the challenge oftherapy for patients with small-celllung cancer (SCLC) who relapse afterfirst-line therapy. Dr. Eckhardt outlinesthe prognostic factors influencingresponse to second-line treatment,survival, and treatment-related toxicity.These prognostic factors includethe response to first-line therapy, theprogression-free interval, and performancestatus. The influence of the chemotherapyregimen and the durationof treatment on symptom palliationand quality of life are also discussed.Dr. Eckhardt provides an excellentsummary of the activity of multipleagents in the second-line setting.

Current agents for the treatment of non-small-cell lung cancer include gemcitabine (Gemzar), paclitaxel (Taxol), docetaxel (Taxotere), vinorelbine (Navelbine), and irinotecan (CPT-11, Camptosar). Experimental agents include

In an era of information "overload" for the practicing oncologist, keeping up with the latest therapies for the many distinct clinical scenarios that arise in daily practice can be quite a challenge. Thus, a concise synthesis of the current knowledge in a field, such as provided in Lung Cancer Therapy Annual 2000 by Drs. Heine Hansen and Paul Bunn, can be quite useful. These authors, whose clinical expertise and contributions to lung cancer therapy are internationally acknowledged, offer a complete review of the literature pertaining to lung cancer therapy from the year 1999, including a review of abstracts from major meetings. A brief summary is provided at the end, outlining standard, accepted strategies based on histologic and stage-by-stage criteria. This text serves as a reference that summarizes the major existing literature, evaluates the strength of the evidence, and makes reasonable recommendations on how to proceed with clinical care.

The activity and toxicity profiles of carboplatin (Paraplatin) and paclitaxel (Taxol) used as single agents in non–small-cell lung cancer made them logical agents for study in combination therapy. Once preliminary trials

In the 1980s, the introduction of cisplatin (Platinol)-based chemotherapy prolonged survival and improved quality of life in patients with stage III and IV non–small-cell lung cancer. More recently, the use of five new