In this issue, Maniwa et al reported on a patient who developed fatal pulmonary toxicity while receiving gemcitabine for treatment of non-small cell lung cancer (NSCLC) (1).

It can be difficult to make a diagnosis of drug-induced pulmonary toxicity in lung cancer patients because of the high incidence of preexisting lung disease, respiratory tract infections, and progressive malignancy in such patients. This patient developed rapidly progressive dyspnea with severe hypoxemia and diffuse infiltrates on radiographic studies 3 days after beginning treatment with gemcitabine. The histological characteristics of his lung tissue were consistent with diffuse alveolar damage (DAD), thus opening up the possibility of various potential etiologies (2, 3). Extensive microbiological analysis of sputum and blood cultures and postmortem examination of the lungs ruled out an infectious etiology. Furthermore, the histopathologic analysis of lung tissue did not reveal any lymphangitic spread of the cancer. Thus, we support the author's conclusion that the acute pulmonary injury with DAD was most likely attributable to gemcitabine.

Gemcitabine is generally a well-tolerated chemotherapeutic agent and active against NSCLC. The spectrum of pulmonary toxicity after treatment with gemcitabine varies from mild dyspnea to a fatal acute respiratory syndrome as shown in the case report of Maniwa et al (1). Recently, the reports of life-threatening pulmonary injury associated with gemcitabine are increasing (4). Although the incidence rate of such serious pulmonary toxicity due to gemcitabine is still less than 1% (5), the clinical picture of dyspnea, hypoxia and the interstitial infiltrates following treatment with gemcitabine should be managed with a high index of suspicion. Although chest radiography is an essential part of the diagnosis, computed tomography (CT) is much more sensitive to drug-induced lung injury than conventional chest radiography and demonstrates related changes earlier. The CT appearance of pulmonary abnormalities can be of value in predicting the prognosis for a patient suffering from drug-induced pulmonary toxicity (6). Thus, chest CT scans should be immediately obtained from patients receiving gemcitabine who present with respiratory insufficiency. We also recommend prompt discontinuation and early treatment with steroids that could be potentially lifesaving.

The use of recent chemotherapeutic agents, which are active against NSCLC, has been found to be associated with pulmonary toxicity with an incidence rate of 1–5%. The incidence of interstitial lung disease (ILD), including interstitial pneumonia (IP) cases in patients being treated with ZD1839 (Iressa, AstraZeneca, Osaka, Japan) is now widely focused (7, 8). By February 2003, AstraZeneca Japan announced 473 patients receiving Iressa had developed ILD of whom 173 died (9). Since about 23,500 patients had received Iressa in Japan at that time, the death rate from ILD associated with Iressa was 0.74% (within the 0.1–1% range categorized as 'infrequent' in accordance with regulatory guidelines). Yet, this is possibly the lower bound since only a proportion of cases are both properly diagnosed and reported. Iressa is an orally active and selective epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that inhibits signal transduction pathways implicated in the proliferation and survival of cancer cells (10). Two large Phase II monotherapy trials (IDEAL 1 and 2) have investigated the efficacy and safety of Iressa in pretreated patients with advanced or metastatic NSCLC (11, 12). Results from IDEAL 1 and 2 were remarkable in part for the fact that substantial responses (objective response rate 11.8%–18.4%) were seen in heavily pretreated patients: over half of patients in IDEAL 2 were receiving Iressa as fourth-line therapy; 44% received Iressa as third-line treatment in IDEAL 1. More remarkable was the fact that these patients showed impressive symptom improvements (symptom improvement rate 40.3–43.1%) and better quality of life (QOL) following treatment with Iressa. Furthermore, Iressa demonstrated a favorable tolerability profile when given as a once-daily chronic treatment. The most common adverse effects were skin rash (most common were grade 1–2 rash) and diarrhea, which were generally mild and seldom required dose interruptions or specific treatment. Thus, Iressa obviously brings big hope to physicians and patients who have been previously treated with platinum-based chemotherapy.

How is the risk and benefit from treatment with Iressa? In the patient with recurrent metastatic NSCLC, the life expectancy is limited and their treatment options are few. The activity of Iressa is certainly exciting, as ~30–50% of this difficult-to-treat patient population appear to benefit in some way from treatment with Iressa, whether it be in response, stability of disease and/or symptom improvement. What predictor could be used to better define the population that would benefit from Iressa is a critical question. Hopefully, this may be partly resolved by correlative studies combined with ongoing and future clinical trials. On the other hand, questions regarding ILD due to Iressa have been argued, although some information might be stretching the truth. The incidence and severity of this toxicity was unpredictable in the previous multicenter clinical trials. What physicians should know is that the rate of fatal ILD due to Iressa is so far comparable to that reported with other current chemotherapies against NSCLC. Further investigation to define not only the exact frequency of ILD associated with Iressa but also the risk factors is undoubtedly warranted. These data would be useful for physicians and patients in the selection of treatment with Iressa because not only the benefit but also the risks of treatment are very important factors. A clear understanding of these issues will hopefully guarantee that many patients with advanced NSCLC will benefit from this highly promising drug in years to come.